The Role of MMP-9 and MMP-9 Inhibition in Different Types of Thyroid Carcinoma

Abstract

Matrix metalloproteinase-9 (MMP-9), one of the most investigated and studied biomarkers of the MMPs family, is a zinc-dependent proteolytic metalloenzyme whose primary function is degrading the extracellular matrix (ECM). It has been proved that MMP-9 expression elevates in multiple pathological conditions, including thyroid carcinoma. MMP-9 has a detectable higher level in malignant or metastatic thyroid tumor tissues than in normal or benign tissues and acts as an additional marker to distinguish different tumor stages because of its close correlations with clinical features, such as lymph node metastasis, TNM stage, tumor size and so on. Natural and non-natural MMP-9 inhibitors suppress its expression, block the progression of diseases, and play a role in therapy consequently. MMP-9 inhibitory molecules also assist in treating thyroid tumors by suppressing the proliferation, invasion, migration, metastasis, viability, adhesion, motility, epithelial-mesenchymal transition (EMT), and other risk factors of different thyroid cancer cells. In a word, discovering and designing MMP-9 inhibitors provide great therapeutic effects and promising clinical values in various types of thyroid carcinoma.

1. Introduction

Matrix metalloproteinases (MMPs), named for their remarkable capacity for extracellular matrix (ECM) degradation, are a category of zin-dependent proteolytic enzymes participating in multiple physiological and pathological processes. The MMPs family consists of 28 members in vertebrates, of which at least 23 proteases are expressed in human tissues. They are generally divided into collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and other MMPs, with six subtypes in total. Among this family, MMP-9 is a broadly concerned molecule of high research values and broad application prospects introduced in the review.

MMP-9, also known as gelatinase B, consists of five main parts as other MMPs: a signal sequence, a propeptide domain, a catalytic domain, a hinge region, and a hemopexin domain. The signal sequence guides the secretion of MMP-9 out of the cells. The propeptide domain, containing a cysteine switch motif PRCGXPD, interacts with zinc ions and prevents the combination of the water molecules to inactive MMP-9. This cysteine switch mechanism is the pivotal issue in controlling the activation of MMP-9, so MMP-3, plasmin, and other proteolytic activators activate MMP-9 through proteolysis or disruption of the propeptide domain. The catalytic domain is the vital part determining the proteolytic activity of MMP-9, formed by the zinc ion binding domain and the active site together. Here unique amino acids play a significant role in enhancing the ability and efficiency of the catalytic process. Three type-Ⅱ fibronectin repeats, similar to MMP-2, assist in the binding to elastin, collagen, gelatin, and other large substrates, becoming a modulator of collagen recognition only present in gelatinases not present in other MMPs. The specific O-glycosylated domain in the hinge region of MMP-9, also called collagen type Ⅴ-like domain on account of the similarity and homology of collagen, is unique in the MMPs family to make MMP-9 highly flexible both intradomain and interdomain. The hemopexin domain not only adds the specificity of MMP-9 in the MMPs family but also plays the following roles: interplay of substrates, combination of inhibitors, attachment of cell surface receptors, and stimulation of auto-activation [1]. The structural model and cartoon model of the multidomain structure of MMP-9 are shown in Figure 1.

Participating in growth, proliferation, apoptosis, migration, invasion, angiogenesis, and many other processes, MMP-9 is confirmed to enroll in a variety of situations clinically, such as tumors [2,3], respiratory diseases [4,5], cardiovascular diseases [6,7], cerebrovascular diseases [8,9], psychiatric disorders [10,11], ophthalmic diseases [12], autoimmune diseases [13] and so on.

2. MMP-9 Inhibition in Different Diseases

2.1. Inhibitory Mechanisms and Representative Agents of MMP-9 Inhibition

Regulating the expression of MMP-9 has been a research hot spot in recent years, and matrix metalloproteinase inhibitors (MMPIs) have been applied to multiple fields. MMP-9 is expressed and controlled in four levels: the transcription of MMP-9 genes, the translation of MMP-9 mRNAs, the proenzyme secretion from neutrophils and other cells, and the activation of the proenzyme to the active form. Based on these mechanisms, MMP-9 can be inhibited in four methods: preventing the production of MMP-9 mRNAs and proMMP-9 at the transcription and translation level, restraining the secretion of proMMP-9, blocking the activation from proMMP-9 to active MMP-9 and inhibiting the activity of active MMP-9 directly.

The first generation of MMPIs, taking batimastat and marimastat as representative agents, has a structure of hydroxamic acid, which helps to bind to zinc ions to inhibit MMP-9 activity. On account of poor solubility, low oral bioavailability, weak specificity, severe musculoskeletal syndrome, and other side effects, these hydroxamic acid derivatives mostly fail in clinical trials. The next generation of MMPIs is invented to be more targeting and efficient, including tanomastat, prinomastat, and rebimastat. However, most of them are also withdrawn from clinical trials [14].

Some MMP-9 inhibitors have poor selectivity and less efficacy, occasionally inhibiting other affinitive MMPs simultaneously because of the structural resemblance, especially the S1’ pocket of MMP-9. The molecular modeling techniques help to design selective MMP-9 inhibitors targeted to anti-cancer therapy.

Therefore, highly selective and specific MMP-9 inhibitors should be discovered and screened in natural compounds or designed by synthetic methods and applied to anti-cancer targeting therapy.

2.2. MMP-9 Inhibition in Different Diseases

2.2.1. Natural MMP-9 Inhibitors or MMP-9 Inhibitory Molecules Applied to Different Diseases

According to a great number of studies, a variety of molecules and compounds show MMP-9 inhibitory effects, roughly divided into natural and non-natural two groups and bringing assistance to disease treatment.

Natural medicines, including plant phenolics, plant flavonoids, phytosterols, and so on, possess great potential in the treatment of tumors, ultraviolet injuries, neurodegenerative diseases, periodontal diseases, ophthalmic diseases, and other situations [15,16,17,18,19]. Compress fluids extraction, thermal processing and its alternatives, drug delivery systems, and other metabolomics techniques assist in investigating the molecular structures of natural compounds and producing the maximum medical effects [20,21]. Therefore, an intake diet of abundant nutritional natural products such as cereal grains, edible flowers and morels shows excellent benefits in health maintenance and multiple disease prevention [22].

Here we enumerate some natural MMP-9 inhibitors and molecules or compounds with MMP-9 inhibitory effects, as shown in Table 1. These natural molecules all show therapeutic effects in a wide range of diseases listed in the table based on effective drug doses.

Green tea polyphenols, the essential bioactive compounds in tea, manifests excellent potential in a variety of conditions. Additionally, among them, epigallocatechin-3-gallate (EGCG) is studied most extensively because of the most generous proportion and the most active biological activity of the total catechins. There is a strong interaction between EGCG and MMP-9, holding the galloyl group of ECG and the propeptide region of MMP-9 to be responsible, which provides them with high binding affinity in silico molecular docking analysis [23]. EGCG shows great significance in periodontal diseases, atherosclerosis, ultraviolet light oxidative damages, and, above all, multiple kinds of tumors through the inhibition of MMP-9. EGCG inhibits the activity of MMP-9 by up-regulating the cell adhesion molecules E-cadherin and β-catenin and suppressing the extracellular signal-regulated kinase (ERK) phosphorylation, restrains the proliferation, invasion, and growth of tumor cells, and becomes a promising medicine for chemoprevention or adjuvant therapy of nasopharyngeal carcinoma [24]. EGCG destabilizes the transcription of MMP-9 to down-regulate its expression in macrophage-like HL-60 myeloid leukemia cells by reducing the gene and protein level of HuR, the MMP-9 mRNA stabilizing nuclear factor. As a result, EGCG can act as an antiangiogenic agent, optimizing the current chemotherapeutic and angiosuppressive treatment of hematological malignancies [25]. EGCG reduces the up-regulated MMP-9 activity induced by ischemia, lessens neuronal damages in hippocampal CA1 and CA2 areas, shrinks the infarct volume, and protects against the ischemia-reperfusion injury, showing neuroprotective effects on transient focal cerebral ischemia [26].

Table 1

Natural MMP-9 inhibitors and inhibitory molecules applied to different diseases.

Reference	Molecules	Research Methods	Research Diseases	Research Subjects	Effective Dose
[18]	Morus alba Stem Extract (MSE)	ELISART-PCR	Periodontitis	THP-1 cells	20 µg/mL, 40 µg/mL
[24]	Epigallocatechin-3-gallate (EGCG)	Gelatin zymography	Nasopharyngeal carcinoma	TW01 cellsNA cells	10 μM, 20 μM, 30 μM, 50 μM
[25]	Epigallocatechin-3-gallate (EGCG)	Gelatin zymography	Myeloid leukemia	HL-60 cells	0.3 µM, 1 µM, 3 µM, 10 µM, 30 µM
[26]	Epigallocatechin-3-gallate (EGCG)	Gelatin zymography	Transient global cerebral ischemia	A C57BL/6 mouse model of transient global cerebral ischemia	50 mg/kg
[27]	Mangiferin	Gelatin zymographyRT-PCRWestern blotting	Astroglioma	U87MG cellsU373MG cellsCRT-MG cells	30–300 μM
[28]	Mangiferin	Gelatin zymographyRT-PCRWestern blotting	Prostate carcinoma	LNCaP cells	400 μM
[29]	Mangiferin	Gelatin zymographyRT-PCR	Glioma	U87 cells	50 μM, 100 μM
[30]	Mangiferin	ELISAWestern blotting	Breast carcinoma	MDA-MB-231 cellsBT-549 cells	12.5 μM, 25 μM, 50 μM
[30]	Mangiferin	Western blotting	Breast carcinoma	An SCID mouse MDA-MB-231 xenograft model	100 mg/kg
[31]	β-sitosterol (SITO)	Western blotting	Colon carcinoma	CT26/luc cells	16 µM
[31]	Liposomal β-sitosterol (LS)	Western blotting	Colon carcinoma	CT26/luc cells	16 µM
[32]	Resveratrol (RES)	Gelatin zymography	Vascular leakage	THP-1 cells	30 μM
[32]	Resveratrol-Linoleate (RES-LA)	Gelatin zymography	Vascular leakage	THP-1 cells	10 μM, 20 μM, 30 μM, 40 μM
[33]	Salvianolic acid A (SAA)	Western blotting	Ischemia reperfusion	An SD rat model of cerebral ischemia reperfusion	5 mg/kg, 10 mg/kg, 20 mg/kg
[34]	Theaflavin	RT-PCR	Periodontitis	A Wistar rat model of ligatured periodontitis	10 mg/mL, 100 mg/mL
[35]	Curcumin	RT-PCRWestern blotting	Atherosclerosis (AS)	THP-1 cells	6.25 µM, 25 µM, 50 µM
[36]	β-elemene	ImmunohistochemistryRT-PCRWestern blotting	Melanoma	A C57BL/6J mouse model with subretinal injection of B16F10 cells	2 μL every 2 days
[37]	Angelica gigas (AG)	RT-PCR	Periodontitis	An SD rat model of ligature-induced periodontitis	1 mg/mL, 100 mg/mL
[37]	Angelica gigas (AG)	ELISA	Periodontitis	HDF cells	1 µg/mL, 10 µg/mL, 100 µg/mL

ELISA: enzyme linked immunosorbent assay; RT-PCR: reverse transcription-polymerase chain reaction.

Mangiferin is a natural polyphenol compound widely derived from higher plants such as Mangifera indica and broadly applied to many diseases. Mangiferin exhibits numerous beneficial pharmacological properties, including antioxidant, anti-inflammatory, anti-diabetic, anti-cancer, and analgesic effects, and some of these functions come to work by the inhibition of MMP-9. Mangiferin suppresses MMP-9 activity in human astroglioma cells at the promoter, mRNA, and protein levels through the inhibition of nuclear factor-κB (NF-κB) and AP-1 binding to the MMP-9 promoter and the down-regulated phosphorylation of Akt and MAP kinases, two upstream signaling molecules of MMP-9. Thus, mangiferin is considered a valuable medical natural product for the therapy of malignant gliomas [27]. Mangiferin inhibits MMP-9 expression in prostate cancer cells by suppressing NF-κB activity [28], inhibits MMP-9 expression in glioma cells by promoting microRNA-15b (miR-15b) level [29], and inhibits MMP-9 expression in breast cancer cells by weakening the activation of β-catenin pathway and reversing the process of epithelial-mesenchymal transition (EMT) [30]. These inhibitory results verify the great anti-tumor potential of mangiferin as an effective chemopreventive agent used in different kinds of tumors.

Various natural molecules possess MMP-9 inhibitory effects. However, high melting point, high molecular weight, poor water solubility, poor gastrointestinal permeability, poor stability, and other shortages limit their bioavailability. Based on the dilemma, liposomes, nanoparticles, and other drug delivery systems have been used to modulate the pharmacokinetics and enhance the targeting ability of the compounds.

β-sitosterol (β-SITO), a member of the phytosterol family, owns various biological properties such as anti-inflammatory, anti-cancer, anxiolytic, cholesterol-lowering, and has been applied to anxiety, diabetes, rheumatoid arthritis (RA), a variety of cancers and many other diseases. However, its poor water solubility and bioavailability make the treatment less effective. Liposomes, hollow spheres consisting of phospholipid bilayers, are usually served as efficient drug delivery vehicles because of the advantage of increasing drug stability, prolonging the circulation time, improving specific uptake, and enhancing water solubility. Liposomal encapsulated β-SITO (LS), synthesized by the thin-film hydration method using egg phosphatidylcholine (EPC), shows better invasion inhibition, lower cytotoxicity, and fewer metastases to other tissues compared with SITO when treating colon carcinoma. The inhibition of MMP-9 and the elicitation of anti-tumor immune response generated by LS further prove it to be a more promising anti-tumor drug [31].

Resveratrol (RES), a natural stilbenoid similar to β-SITO, shows great anti-oxidant and anti-cancer effects as well as poor pharmacokinetics, potency, and bioavailability. Novel RES-lipid conjugates, such as resveratrol-linoleate (RES-LA), are lipophilic derivatives of RES synthesized by enzymatic and chemical synthesis. RES-LA represents better lipophilicity and bioavailability, more substantial cell membrane penetration, and greater inhibition of MMP-9 by inactivating ERK1/2 and JNK1/2 MAP kinase signaling pathways compared with RES in the inflammatory treatment. As a result, RES-LA is used to preserve the connecting integrity between endothelial cells, reduce pathological endothelial permeability and mitigate vascular endothelial dysfunction under inflammation [32].

These circumstances suggest that natural products indeed possess MMP-9 inhibitory effects in plenty of disorders. Novel natural molecule conjugates loading on drug delivery systems should be designed and synthesized to improve the bioavailability and enhance the inhibition of MMP-9 with a broad treating application prospect.

2.2.2. Non-Natural MMP-9 Inhibitors or MMP-9 Inhibitory Molecules Applied to Different Diseases

Another group of MMP-9 inhibitors is non-natural synthetic molecules, as shown in Table 2.

SB-3CT, a potent and selective synthetic inhibitor targeting MMP-2 and MMP-9, is commonly used in brain damage caused by various reasons. Through antagonizing the increasing level of MMP-9, SB-3CT provides behavioral protection, preserves hippocampal neurons, prevents cell apoptosis, attenuates brain infarct volumes, improves neurobehavioral outcomes, and ameliorates neurobehavioral prognosis of brain injuries caused by trauma, embolism and hypoxia [38]. In addition to cerebrovascular diseases, SB-3CT shows anti-tumor ability in melanoma and lung cancer by inhibition of MMP-9 through the reduction of programmed death ligand 1 [66] and anti-inflammation ability in inflammatory corneal neovascularization by suppression of MMP-9 and VEGF-C together to reduce corneal lymphangiogenesis and macrophage infiltration [40].

According to pharmacokinetics studies, SB-3CT is poorly water soluble, and it primarily metabolizes to p-hydroxy SB-3CT on account of the oxidation of the terminal phenyl, which shows a more powerful and efficient ability to inhibit MMP-9. To enhance the inhibitory effects, an innovative prodrug strategy emerges for better water solubility and therapeutic outcomes. That is synthesizing the O-phosphate prodrug of p-hydroxy SB-3CT. This prodrug has few effects of its own but hydrolyzes to p-hydroxy SB-3CT in human blood and crosses the blood-brain barrier (BBB) easily, making therapeutic significance in cerebral diseases [67].

A portion of synthetic MMP-9 inhibitors is designed to target two or more enzymes simultaneously because of their similar structures and functions. AZD1236, a selective oral inhibitor of MMP-9 and MMP-12, has been applied to the treatment of spinal cord injury through suppression of edema, pain sensation, blood-spinal cord barrier (BSCB) breakdown, and improvement of electrophysiological, sensory, and motor functions [41]. It can also be used in the adjuvant therapy of moderate to severe chronic obstructive pulmonary disease (COPD) safely and tolerably [42,68]. AZ11557272, a dual MMP-9 and MMP-12 inhibitor, abolishes smoke-induced lavage inflammatory cells and serum tumor necrosis factor α (TNFα), ameliorates morphological emphysema targets of COPD, and participates in the therapeutic process [43]. AQU-118, an oral inhibitor of MMP-2 and MMP-9, reduces mechanical allodynia and caspase-3 expression in the dorsal root ganglion (DRG) of rats to treat spinal nerve ligation-induced neuropathic pain. More research should be performed to determine whether AQU-118 is efficient and applicable to treating neuropathic pain in humans [69].

The majority of MMP-9 inhibitors are designed to bind to the highly conserved enzyme catalytic active site of MMP-9. However, this kind of inhibitory mechanism fails in clinical trials mainly because of low specificity and high toxicity, for the inhibitors not only bind to the zinc ion of MMP-9 but also combine with other heavy metals in different proteins.

The N-terminal domain of TIMP-2 (N-TIMP2), remaining strong inhibitory effects of various MMPs, is chosen as a scaffold to design novel high-affinity and high-specificity MMP inhibitors. Jason Shirian constructs a small combination library of abundant N-TIMP2 mutants and selects N-TIMP2 variants targeting MMP-9 and MMP-14, using computational design and yeast surface display (YSD) technology. The specific inhibitor, converted from a broad inhibitor, exhibits a thousand-fold binding capacity over other MMPs and is a successful example of diagnostic and therapeutic tools targeting MMP-9 to inhibit the development of diseases [70].

Differing from the mechanisms of conventional MMP-9 inhibitors, novel inhibitors describe innovative and characteristic inhibitory mechanisms, showing a promising application prospect clinically. (I-3, II-3)-biacacetin is a natural product-like biflavone synthesized by one-pot protocol, an oxidative dimerization synthesis of poly-substituted diaryl-1,3-diketones and cerium ammonium nitrate. The molecule shows no hydrogen bonding with MMP-9 but hydrophobic interactions with the amino acid residues and binds outside the S10 active site instead of interacting with the zinc ion in the catalytic site, in silico docking analysis [44].

JNJ0966 is a highly selective and safe MMP-9 inhibitor. The compound interacts with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, distinct from the catalytic domain, inhibits the activation of MMP-9 zymogen and prevents the conversion to the catalytically active enzyme. JNJ0966 has obtained prominent curative effects in the mouse model of autoimmune encephalomyelitis, which represents a significant advance in the field of MMP-9 inhibition use in clinical treatment [71].

2.2.3. MMP-9 Inhibitors or MMP-9 Inhibitory Molecules Involved in Clinical Trials

MMP-9 inhibitors have been used in clinical trials a great many times, experiencing many failures. Currently, several phase 1 and phase 2 clinical trials have obtained a few results. Curcumin is involved in a randomized controlled clinical trial designed for investing the effects on MMP-9 in patients with coronary artery diseases. The results show that curcumin can prevent cardiovascular diseases by declining the expression and activity of MMP-9 [72]. GS-5745, an anti-MMP-9 monoclonal antibody, is involved in a phase 1 randomized clinical trial to evaluate the safety and efficacy of treating ulcerative colitis [73]. COL-3, an MMP inhibitor, is involved in a phase 1 clinical trial to determine its doses and toxicities in patients with refractory metastatic tumors [74]. Andecaliximab, an inhibitor of MMP-9, is involved in a phase 2 randomized open-label clinical trial to estimate the therapeutic effects on advanced gastric carcinoma, comparing using nivolumab alone with using nivolumab plus andecaliximab together. The combination treatment of these two drugs has a favorable safety with no more remarkable effects than the single treatment [75].

3. MMP-9 Expression in Thyroid Carcinoma

3.1. Introduction of Thyroid Carcinoma Diagnosis

Thyroid carcinoma (TC), the most common endocrine cancer, has a rising incidence and mortality increased by 60–200% during nearly 30 years from 1990 to 2017, with an apparent higher incidence in females than in males, revealing a distinct epidemiological pattern [76].

Thyroid tumors are classified into several categories: thyroid nodules, mostly small, non-palpable and benign lesions; differentiated thyroid cancer (DTC), originating from thyroid epithelial cells and accounting for more than 95% of malignant cases; anaplastic thyroid cancer (ATC), a rare but dangerous form with a high possibility of metastasis, accounting for 1%; medullary thyroid cancer (MTC), originating from the parafollicular neuroendocrine cells of thyroid and accounting for 1–2% [77]. Papillary thyroid cancer (PTC) is the leading histological subtype of overall thyroid tumors, followed by follicular thyroid cancer (FTC). The incidence of PTC increased visibly and systematically with large variability by sex in the 25 observed countries during the period from 1998 to 2012 [78].

Fine-needle aspiration (FNA) is a confirmatory detection test for the diagnosis of thyroid cancer, with high sensibility and high specificity, widely accepted and used around the world. However, this technique highly depends on the standard meticulous operation and considerable experience of operators [79]. In addition, it is an invasive detection with possibilities of misdiagnosis, risks of hemorrhage and metastasis after the procedure, and feelings of pain and anxiety [80].

In order to develop a new safe, and accurate diagnosis approach, tumor biomarkers receive lots of attention. Calcitonin levels in medullary thyroid cancer, BRAFV600E mutations in papillary thyroid cancer, RAS mutations in follicular thyroid carcinoma, and levels of thyroglobulin (TG) and thyroid stimulating hormone (TSH) are all significant biomarkers.

This review describes MMP-9 as a tumor marker for thyroid cancer, for this protein is involved in multiple aspects of the progression of the tumor.

3.2. MMP-9 Expression Levels in Thyroid Carcinoma

According to a variety of studies, MMP-9 expresses higher in thyroid tumor tissues than in non-tumor tissues, in malignant tumors than in benign tumors, in metastatic tumors than in non-metastatic tumors, and before operation than after operation in general, mainly detected by immunohistochemistry (IHC), gelatin zymography, western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA), as shown in Table 3.

Therefore MMP-9, showing high malignant potential in thyroid carcinoma, can be considered as a kind of biomarker assisting in diagnosing the pathological type of tumors, assessing the metastatic status, and evaluating the therapeutic effects of the operation.

Various types of research show close correlations between MMP-9 levels and clinicopathological characteristics, such as lymph node metastasis, extrathyroidal invasion, degree of tumor infiltration, TNM stage, tumor size, distant metastasis, age, and lymphovascular invasion, as shown in Table 4.

Jelena Roncevic observes that high levels of MMP-9 in PTC patients with unfavorable clinicopathological features, including the presence of lymph node metastasis, extrathyroidal invasion, large tumor size, and advanced TNM stage, which confirms the important role of MMP-9 in the progression of tumor and the prognosis of patients [81]. Xingkai Liu discovers that PTC patients with central and lateral lymph node metastasis have an increasing level of MMP-9 and an advanced TNM stage, making MMP-9 assessment a supplementary diagnosing and predicting tool clinically [82]. Another research proves that only active patterns of MMP-9, rather than the total levels of MMP-9, have significant associations with lymph node metastasis, extrathyroidal invasion, and degree of tumor infiltration. The ratio of MMP-9 activation also plays an important role, providing new ideas for the detection of active MMP-9 instead of total MMP-9 in a further study [83].

Some researchers have analyzed the clinical significance of MMP-9 levels to predict the prognosis of thyroid carcinoma in longitudinal studies. As for the prognosis of diseases, two investigation objects are taken into analysis generally, recurrence and survival time without structurally persistent/recurrent disease (SPRD). After a period of no evidence of the disease, unexpected structural diagnostic evidence is named recurrence. The period from premier treatment to the occurrence of structurally persistent disease, recurrent disease, or last follow-up is investigated as survival time without SPRD. Dahai Xu finds a significantly higher MMP-9 score in patients with SPRD than without SPRD, representing MMP-9 as a potential and supplementary tool for prognosis prediction [84]. Daniel Buergy detects that increasing levels of MMP-9 are consistent with the metastasis of the tumor and the tumor recurrence locally, which indicates its predictive relevance to tumor progression and prognosis [85].

MMP-9 activity can also distinguish sporadic PTC and radiation-associated PTC using immunochemistry clinically. Patients diagnosed with PTC on account of exposure to the external and internal radiation of the Chernobyl nuclear accident have an abundant expression of MMP-9 in tumor tissues, demonstrating the high aggression of the tumor [86]. The increased incidence of thyroid cancer after the accident results from iodine deficiency in the contaminated territories, contributing to more frequent thyroid goiter and thyroid nodules.

Besides being relevant to clinicopathological factors alone, MMP-9 also shows significant relationships with other molecules. There is a statistically significant correlation between the expression of MMP-9 and VEGF-C, the simultaneous levels of which have significant effects on lymph node metastasis, TNM stage, and degree of tumor infiltration. This condition explains that MMP-9 contributes only a few parts of the tumor progression and generally works with other molecules together to regulate the tumors [87].

Although a majority of research has supported that MMP-9 expression levels are relevant to high metastatic potential and poor prognosis closely, there are still several studies that find no statistical significance between MMP-9 and the metastasis of tumors [88,89,90].

Table 3

MMP-9 expression levels in thyroid carcinoma.

Reference	Type of Thyroid Carcinoma	Type of Samples	Research Objects	Research Methods	MMP-9 Expression Data	MMP-9 Expression Levels
[91]	PTC	Tissue	86 patients with PTC	ImmunohistochemistryGelatin zymographyWestern blotting	IHC positive staining ratio:PTC tumor tissues: 71/86 (82.56%)PTC non-tumor tissues: 53/86 (61.63%)	MMP-9 had a statistically significant higher level in tumor tissues than non-tumor tissues in PTC (p < 0.05).
[92]	PTC	Tissue	25 patients with non-metastatic small PTC19 patients with metastatic small PTC	Immunohistochemistry	IHC scores:Non-metastatic PTC tumor tissues: 1.44Non-metastatic PTC non-tumor tissues: 0.80Metastatic PTC tumor tissues: 2.00Metastatic PTC non-tumor tissues: 0.82	MMP-9 had a statistically significant higher level in tumor tissues than non-tumor tissues in both non-metastatic PTC (p < 0.01) and metastatic PTC (p < 0.001).
[93]	PTC	Tissue	83 patients with PTC	ImmunohistochemistryRT-PCR	IHC positive staining ratio:PTC tumor tissues: 48/83 (57.83%)PTC non-tumor tissues: 2/83 (2.41%)	MMP-9 had a statistically significant higher level in tumor tissues than non-tumor tissues in PTC (p < 0.001).
[94]	PTC	Tissue	50 patients with PTC	ImmunohistochemistryRT-PCR	/	MMP-9 had a statistically significant higher level in tumor tissues than non-tumor tissues in PTC (p = 0.01).
[95]	PTC	Tissue	60 patients with PTC30 patients with MNG	ELISART-PCR	mRNA level:PTC tumor tissues: 8.05 ± 16.48PTC non-tumor tissues: 3.06 ± 3.63Protein level:PTC tumor tissues: 429.60 ± 288.54PTC non-tumor tissues: 223.15 ± 137.68	MMP-9 had a statistically significant higher level in tumor tissues than non-tumor tissues in PTC (p < 0.05).
[82]	PTC	Tissue	112 patients with PTC42 patients with BTN	Immunohistochemistry	IHC scores:PTC tumor tissues: median 4.0, IQR 2.0–8.0BTN tumor tissues: median 1.0, IQR 0.0–1.0	MMP-9 had a statistically significant higher level in PTC tissues than in BTN tissues (p < 0.001).
[84]	PTC	Serum	182 patients with PTC86 patients with BTN62 HCs	ELISA	Protein level:PTC serums: median 79.45, IQR 64.06–113.15BTN serums: median 47.35, IQR 38.05–68.14HC serums: median 47.71, IQR 36.70–59.52	MMP-9 had a statistically significant higher level in PTC serums than in BTN serums (p < 0.001) and HC serums (p < 0.001).
[85]	PTCMTCFTCATC	Tissue	47 patients with TC22 patients with FA	ELISA	/	MMP-9 had a statistically significant higher level in TC tissues than in FA tissues (p = 0.001).
[95]	PTC	Tissue	60 patients with PTC30 patients with MNG	ELISART-PCR	mRNA level:PTC tumor tissues: 6.77 ± 7.16MNG tumor tissues: 2.49 ± 3.70Protein level:PTC tumor tissues: 429.60 ± 288.54MNG tumor tissues: 218.14 ± 113.74	MMP-9 had a statistically significant higher level in PTC tissues than in MNG tissues (p < 0.05).
[96]	FTC	Tissue	6 patients with WIFC15 patients with MIFC19 patients with FA10 patients with AG	Immunohistochemistry	IHC positive staining ratio:MIFC tumor tissues: 13/15 (86.67%)FA tumor tissues: 11/19 (57.89%)AG tumor tissues: 3/10 (30.00%)	MMP-9 had a statistically significant higher level in MIFC tissues than in FA tissues (p < 0.05) and AG tissues (p < 0.005).
[97]	PTC	Tissue	66 patients with PTC40 patients with BTN	Immunohistochemistry	IHC positive staining ratio:PTC tumor tissues: 61/66 (92.42%)BTN tumor tissues: 8/40 (20.00%)	MMP-9 had a statistically significant higher level in PTC tissues than in BTN tissues (p < 0.001).
[98]	DTC	Serum	57 patients with DTC49 patients with BTN20 HCs	ELISART-PCR	Protein level: Mean ± SDDTC serums: 134.70 ± 32.52BTN serums: 47.60 ± 20.10HC serums: 40.52 ± 10.20	MMP-9 had a statistically significant higher level in DTC serums than in BTN serums (p < 0.05) and HC serums (p < 0.05).
[99]	PTC	Serum	41 patients with PTC56 patients with BTN	ELISA	Protein level:PTC serums: 299.98 ± 70.48BTN serums: 126.62 ± 19.26	MMP-9 had a statistically significant higher level in PTC serums than in BTN serums (p < 0.01).
[100]	PTC	Plasma	30 patients with PTC30 patients with BTN23 HCs	ELISA	Protein level: Mean ± SDPTC plasma: 72.3 ± 23.3BTN plasma: 23.0 ± 2.2HC plasma: 22.1 ± 3.0	MMP-9 had a statistically significant higher level in PTC plasma than in BTN plasma (p < 0.05) and HC plasma (p < 0.05).
[101]	PTCFTCATC	Cell	IHH-4 cellsFTC-133 cells8505C cellsHT-ori3 cells	Western blotRT-PCR	Protein level (the relative gray value):HT-ori3 cells: 1.01 ± 0.43IHH-4 cells: 6.59 ± 1.24FTC-133 cells: 5.10 ± 0.918505C cells: 5.42 ± 0.86mRNA level:HT-ori3 cells: 1.01 ± 0.09IHH-4 cells: 4.56 ± 0.61FTC-133 cells: 3.41 ± 0.428505C cells: 2.79 ± 0.26	MMP-9 had a statistically significant higher level in IHH-4 cells, FTC-133 cells, and 8505C cells than HT-ori3 cells (p < 0.05).
[98]	DTC	Serum	57 patients with DTC49 patients with BTN20 HCs	ELISART-PCR	Protein level:DTC preoperative serums: 134.70 ± 32.52DTC postoperative serums (1 month after surgery): 51.46 ± 18.34	MMP-9 had a statistically significant higher level in DTC serums before operation than after operation (p < 0.05).
[99]	PTC	Serum	41 patients with PTC56 patients with BTN	ELISA	Protein level:PTC preoperative serums: 299.98 ± 70.48PTC postoperative serums (3 months after surgery): 201.65 ± 65.31PTC postoperative serums (6 months after surgery): 184.64 ± 64.82PTC postoperative serums (12 months after surgery): 169.07 ± 64.16	MMP-9 had a statistically significant higher level in PTC serums before operation than after operation (p < 0.05).
[102]	PTC	Tissue	27 patients with metastatic PTC31 patients with non-metastatic PTC	Immunohistochemistry	IHC positive and strongly positive staining ratio:Metastatic PTC tumor tissues: 19/27 (70.37%)Non-metastatic PTC tumor tissues: 11/31 (35.48%)	MMP-9 had a statistically significant higher level in PTC tumor tissues with metastasis than without metastasis (p < 0.05).
[103]	PTC	Tissue	71 patients with cervical lymph node metastatic PTC85 patients with non-metastatic PTC	Immunohistochemistry	IHC intense positive staining ratio:Metastatic PTC tumor tissues: 17/21 (80.95%)Non-metastatic PTC tumor tissues: 4/21 (19.05%)	MMP-9 had a statistically significant higher level in PTC tumor tissues with metastasis than without metastasis (p = 0.000).
[104]	PTC	Tissue	17 patients with CPTC25 patients with FPTC	Immunohistochemistry	IHC positive staining ratio:FPTC tumor tissues: 20/25 (80.00%)CPTC tumor tissues: 17/17 (100.00%)	MMP-9 had a statistically significant higher level in CPTC tissues than in FPTC tissues (p < 0.004).

PTC: papillary thyroid cancer; FTC: follicular thyroid cancer; MTC: medullary thyroid cancer; ATC: anaplastic thyroid cancer; MNG: multinodular goiter; WIFC: widely invasive FTC; MIFC: minimally invasive FTC; FA: follicular adenoma; AG: adenomatous goiter; BTN: benign thyroid nodule; HC: healthy control; CPTC: classical PTC; FPTC: follicular PTC.

Table 4

Correlations between MMP-9 levels and clinicopathological characteristics.

Reference	Type of Thyroid Carcinoma	Type of Samples	Lymph Node Metastasis (LNM)	Extrathyroidal Invasion (EI)	Degree of Tumor Infiltration (DTI)	TNM Stage	Tumor Size	Distant Metastasis	Age	Lymphovascular Invasion
[81]	PTC	Tissue	p = 0.028	p = 0.001		p = 0.005	p = 0.031
[82]	PTC	Tissue	Central LNMp = 0.002Lateral LNMp < 0.001			p = 0.004
[83]	PTC	Tissue	p = 0.004	p < 0.001	p < 0.001				p = 0.034
[91]	PTC	Tissue	p = 0.014
[93]	PTC	Tissue	p < 0.001 (protein)p = 0.038 (mRNA)				p = 0.008
[94]	PTC	Tissue		p = 0.019	p = 0.019
[95]	PTC	Tissue				p = 0.011 (mRNA)p = 0.001 (protein)			p = 0.015 (mRNA)p = 0.001 (protein)	p = 0.003 (mRNA)p = 0.036 (protein)
[97]	PTC	Tissue				p = 0.006	p < 0.001		p = 0.003
[105]	FTC	Tissue					p = 0.001	p = 0.016
[84]	PTC	Serum	Lateral LNM p < 0.001	p = 0.022		p < 0.001	p = 0.029	p = 0.003
[98]	DTC	Serum	p < 0.05		p < 0.05	p < 0.05	p < 0.05
[100]	PTC	Plasma	p < 0.001	p = 0.037		p = 0.003	p = 0.002	p = 0.034

These results may be due to the following several reasons: 1. The detection methods of MMP-9, such as immunohistochemistry, are mostly semi-quantitative, requiring the subjective judgments of researchers, which may have different influences on the final results. 2. The research objects are different in different studies. Some studies focus on the differences between metastatic and non-metastatic tumors rather than malignant tumors and benign disease, which shows inconsistency in the final conclusions.

Coincidentally, Ruxandra Dobrescu draws a conclusion that serum MMP-9 levels not only show no differences between benign and malignant patients but also differ insignificantly in ages, histological subtypes, TNM stages, multifocal or unifocal tumors, small or large tumor sizes, lymph node metastasis, and extrathyroidal extension. As for these contradictory results compared to previous studies, researchers demonstrate four reasons: 1. The most representative and most substantial evidence comes from MMP-9 detection in tumor tissues, and the serum levels only partly reflect the tumor situation. 2. Increasing levels of MMP-9 are involved in various processes containing inflammation, autoimmune disorders, and degenerative diseases, which should also be taken into account. 3. ELISA technology measures the total of proMMP-9, active MMP-9, degradation products, and other complexes instead of a single molecule. 4. The study uses serums as samples, which may provide different results from plasma samples because of coagulants and anticoagulants [106].

MMP-9 participates in a series of signaling pathways in thyroid carcinoma, as shown in Table 5. Possessing a steadily increasing incidence, thyroid cancer has relatively low mortality on the contrary compared with other malignant tumors. Hence the most significant and challenging focus is not operating a perfect thyroidectomy operation on all patients but treating them by grading diagnosis and grading therapy in order to avoid overtreatment of patients with low risks and identify advanced patients with high stakes, metastatic potential, and poor prognosis [77].

The detection of MMP-9 levels plays a vital role in this matter. In most cases, high MMP-9 levels in tumor tissues or serums relate to an advanced stage and high risks, and patients in these circumstances need more aggressive and rapid treatment approaches. In other words, adding MMP-9 detection to preoperative examinations may assist in grading the patients who require different patterns of therapy, such as thyroidectomy surgery or radioiodine therapy. Additionally, a quick and accurate MMP-9 detection during the operation period time may help surgeons judge the surgery forms and scopes, such as lymph node dissection area and the extent of surgical thyroid resection.

4. MMP-9 Inhibition in Thyroid Carcinoma

4.1. Introduction of Thyroid Carcinoma Therapy

The treatment of thyroid cancer is a multidisciplinary cooperative process. Thyroidectomy in the open field or under the endoscope is the most common method to treat differentiated thyroid carcinoma, sometimes accompanied by the problem of overtreatment. Radioactive iodine therapy is a preferred adjuvant therapy for remnant ablation and recurrent tumor administered after surgery, with an increased risk of secondary malignancies development. TSH suppression therapy is chiefly used in high-risk patients with incomplete resection, tumor invasion, or distant metastasis, which may lead to side effects such as osteoporosis. Chemotherapy after surgery is a treatment alternative, mostly for poorly differentiated anaplastic cancer. Doxorubicin, sorafenib, axitinib, and other chemotherapeutic agents have shown some promise of the tumor holding a very poor prognosis [120,121].

Apart from the above treatment methods, MMP inhibitors, especially inhibitors for MMP-9, which have been confirmed to link with thyroid cancer, can act as targeting drugs with promising prospects for future development. These inhibitory molecules or compounds exhibit specific targeting ability in the signaling pathways of tumors and have achieved good curative effects in vivo and in vitro, which can be an effective supplementary therapy for thyroid cancer.

4.2. MMP-9 Inhibition in Thyroid Carcinoma

4.2.1. Natural MMP-9 Inhibitors or MMP-9 Inhibitory Molecules Applied to Thyroid Carcinoma

Similar to MMP-9 inhibitors applied to different diseases and situations, MMP-9 inhibitors and inhibitory molecules also work in thyroid carcinoma and can be divided into two groups, natural and non-natural, as shown in Table 6 totally. The mechanisms of MMP-9 inhibition in different aspects are shown in Figure 2.

Curcumin, a constituent of the traditional medicine known as turmeric, shows potential therapeutic effects on various diseases such as cardiovascular diseases, aging-related diseases, and a wide range of cancers, including colorectal cancer, breast cancer, and thyroid cancer certainly. Curcumin inhibits the metastasis of K1 papillary thyroid cancer cells via down-regulating the expression of MMP-9 and up-regulating the expression of E-cadherin, which consequently suppresses the epithelial-mesenchymal transition (EMT) and reduces the viability and migration of tumor cells [122]. Moreover, hypoxia, a common condition essential for tumor metastasis, stimulates the expression of transcription factor hypoxia-inducible factor 1 (HIF-1) in tumor cells and activates many genes of proteases, including MMP-9. Curcumin decreases reactive oxygen species (ROS) induced by hypoxia, suppresses the expression of HIF-1 in K1 cancer cells, enhances E-cadherin expression, and inhibits MMP-9 activity. As a result, curcumin alleviates the migration of K1 cells under hypoxic conditions, showing anti-cancer and anti-metastasis functions in PTC [123]. MicroRNAs (miRNAs or miRs) participate in a variety of tumors, acting as either oncogenes or tumor suppressors. Curcumin up-regulates miR-301a-3p, which directly targets STAT3 (signal transducer and activator of transcription 3) and suppresses its expression. MiR-301a-3p, a tumor suppressor, targets STAT3 directly and suppresses the protein expression. By regulating the miR-301a-3p/STAT3 axis, curcumin increases the expression of miR-301a-3p, decreases the expression of MMP-9 and EMT markers, and inhibits the viability, migration, and invasion of TPC-1 papillary thyroid cancer cells [124]. These consequences all prove that curcumin can be regarded as a high-efficiency and high-safety natural MMP-9 inhibitor, exhibiting great significance in the treatment of papillary thyroid cancer in many aspects.

Quercetin is one of the most abundant polyphenolic flavonoids present in grapefruits, onions, berries, and other fruits and vegetables. Applied to the therapy of plenty of diseases, quercetin shows vast therapeutic potential, such as anti-viral, anti-cancer, anti-oxidant, anti-diabetic, and so on. NIS (Sodium iodide symporter) mediates the accumulation of iodide in thyrocytes and promotes ablative therapy with radioiodine. A reduction of NIS in some PTC patients leads to low effective radioiodine therapy. Quercetin increases the expression and function of NIS, inhibits MMP-9 activity, and enhances E-cadherin activity so as to achieve strong therapeutic effects in the process of the suppression of cell migration and EMT [133]. As a consequence, thyroid cancer patients who need radioiodine treatments are suggested to take quercetin as a kind of adjuvant medicine to improve the curative effects.

Panax ginseng is a well-known Chinese traditional herb usually used as a kind of tonic, and ginsenoside is the bioactive constituent extracted from the root or stem of it. Ginsenoside has many beneficial pharmacological properties, especially anti-metastatic and anti-inflammatory effects intimately related to the inhibition of MMPs through modulating the signaling pathways [141]. For example, ginsenoside Rg1 suppresses the invasion and migration of breast cancer cells mainly via the down-regulation of MMP-9, which is mediated by NF-κB [142]. When used in thyroid cancer, ginsenoside Rg3 shows metastasis suppression effects mainly through the mechanism of alternating actin skeleton of tumor cells and destroying the function. Ginsenoside Rg3 also decreases the levels of MMP-2, MMP-9, Rac-1, and Cdc42, blocking lymph node metastasis in PTC and angiogenesis in ATC [128]. As a consequence, ginsenoside compounds can be considered as MMP-9 inhibitors applied to treat different kinds of disorders, including thyroid cancer.

4.2.2. Non-Natural MMP-9 Inhibitors or MMP-9 Inhibitory Molecules Applied to Thyroid Carcinoma

Apart from natural MMP-9 inhibitors, there are some non-natural molecules possessing MMP-9 inhibitory abilities in thyroid cancer cells, although they are not mainly used in the treatment of thyroid carcinoma.

Differentiation therapy is a therapeutic intervention measure promoting the differentiation of tumor cells rather than killing cells directly by targeting tumor-initiating stem cells. Histone deacetylase (HDAC) inhibitors have been brought into focus as anti-proliferation agents in the differentiation treatment of cancer for their potential to induce cell apoptosis, promote cell differentiation and block the cell cycle. Valproic acid (VPA) represents one of the most efficient broad-spectrum antiepileptic drugs and exerts therapeutic effects on mania as well. Exposure to VPA may increase the risk of autism spectrum disorders (ASD) and teratogenicity. Vahid Haghpanah discovers that VPA, as a histone deacetylase inhibitor, reduces the expression of MMP-2 and MMP-9, declines stem cell markers and tumor aggressiveness, and stimulates the anaplastic thyroid cancer cells to redifferentiate. Relying on this specific function, VPA can be used in the differentiation therapy of highly aggressive and poorly differentiated thyroid cancer [137].

Sevoflurane is an effective volatile anesthetic agent widely used both in adults and in children, with potential neurotoxicity leading to postoperative cognitive dysfunction (POCD) under some circumstances. Y. LI finds that by suppressing the expression of miR-155, sevoflurane inhibits the protein expression of MMP-2 and MMP-9, limits cell migration and invasion, and promotes cell apoptosis in papillary thyroid cancer cells. In a word, sevoflurane can be a good choice for the anesthesia of thyroid cancer surgery to improve the prognosis of patients [135].

Celecoxib is a cyclooxygenase-2 (COX-2) selective suppressor that exhibits anti-tumor potential in various types of tumors, such as intestinal cancer, skin cancer, and breast cancer, and anti-inflammatory potential in various types of arthritis such as osteoarthritis, rheumatoid arthritis, and musculoskeletal arthritis. When applied to the treatment of thyroid cancer, celecoxib decreases the protein and mRNA levels of COX-2, MMP-9, and VEGF in human medullary thyroid cancer TT cells in vitro and in the nude mice model of human medullary thyroid cancer in vivo. As a result, celecoxib inhibits growth and angiogenesis by decreasing the production of prostanoid-like COX-2.

In addition to chemical molecules, there are some other approaches inhibiting the expression of MMP-9 and assisting in the treatment of thyroid carcinoma. Due to advanced ideas and technologies, non-thermal atmosphere pressure plasma (NTP) has been generated at room temperature and applied to multiple fields, such as the prevention of plant diseases, inactivation of bacteria, activation, and proliferation of human adult stem cells, and plasma treatment of a few kinds of tumors. NTP decreases the activity of MMP-2, MMP-9, and uPA, inhibits Akt and ERK signaling, and rearranges the cytoskeleton regulated by the FAK/Src complex resulting in changes in cellular morphology. Under these mechanisms, NTP exerts anti-tumor effects by inhibiting the invasion and metastasis of papillary thyroid cancer cells and opens up a novel strategy to treat invasive and metastatic thyroid carcinoma as a consequence [143].

Seeing the MMP-9 inhibitors applied to thyroid cancer, we find that these kinds of inhibitory molecules get involved in a series of critical steps in the tumor progression, for instance, in proliferation, migration, invasion, metastasis, angiogenesis, apoptosis, redifferentiation and epithelial-mesenchymal transition (EMT).

EMT is a reversible cellular program involved in embryonic development, wound healing, and cancer progression. Under normal situations, epithelial cells are conjoined together laterally to form polar sheets displaying polarity, whereas mesenchymal cells exhibit no conjunctions with adjacent cells, completely on the contrary. In the context of tumors, epithelial tumor cells turn into mesenchymal cells through diminishing cellular conjunctions, decreasing focal adhesion, down-regulating epithelial markers such as E-cadherin and Keratin, up-regulating mesenchymal markers such as N-cadherin and vimentin, increasing cell mobility, remodeling cytoskeleton, and degrading extracellular matrix under the assistance of MMP-9 and other MMPs [144].

Under the background of thyroid cancer, high levels of MMP-9 promote the EMT process, bound up with the invasion, migration, metastasis, and apoptosis of thyroid cancer cells. Inhibition of MMP-9 suppresses the occurrence of EMT and consequently retards the tumor progression, increases the survival time, and improves the survival quality of patients, which further proves the therapeutic abilities of MMP-9 inhibitors used in thyroid cancer.

Non-coding RNAs refer to RNAs that are transcribed from genes but are not translated into proteins, performing their biological functions at the RNA level. MicroRNAs (miRNAs) are a class of non-coding single-stranded RNA molecules which are about 22 nucleotides in length. MiRNAs target tumor suppressors or promoters to adjust the progression of the tumor, exhibiting inhibitory or accelerating effects conversely due to different molecules. MiR-205 declines MMP-9 expression and suppresses angiogenesis and EMT, which can be an alternative therapeutic strategy to treat ATC [145]. In addition, miR-214 [146], miR-203 [147], and several miRNAs have similar abilities. On the contrary, miR-106a-5p increases MMP-9 levels, promotes the activity, migration, and invasion of PTC cells, and inhibits cell apoptosis [148]. Long non-coding RNAs (lncRNAs) have a length of about 200 nucleotides, participating in cell progression and disease development. LncRNA UCA1 has a high level in PTC consistent with high expression of MMP-9, which is related to tumor stages and lymph node metastasis [149]. LncRNA LINC0031 reduces the expression of MMP-9, suppresses the activation of the P13K/Akt signaling pathway, and inhibits tumor progression [150]. Circular RNAs (circRNAs) are produced by the circulation mechanism of exons. CircRNA DOCK1 not only becomes enriched in tumor tissues but also induces the accumulation of MMP-9, contributing to thyroid carcinoma [151].

5. Conclusions and Prospects

The review focuses on the role of MMP-9 as a biomarker and MMP-9 inhibition as a treatment method in various diseases, taking thyroid carcinoma as an instance. There are generally high MMP-9 mRNA or protein levels in thyroid tumor tissues, malignant tumor tissues, metastatic tumor tissues, and other samples with a high degree of malignancy rather than a low degree. What is more, high expression of MMP-9 has an intimate relationship with the presence of lymph node metastasis, the presence of distant metastasis, extrathyroid invasion, high degree of tumor infiltration, advanced TNM stage, a large tumor size, the aged population and other clinical factors that exhibit poor prognosis.

The review summarizes and enumerates MMP-9 inhibitors or MMP-9 inhibitory molecules applied to thyroid cancer and other disorders. The molecules can be roughly divided into natural groups and non-natural groups, both of which participate in multiple aspects of diseases and show effective therapeutic effects. Especially in thyroid tumors, natural MMP-9 inhibitors represent comprehensive curative potential in different kinds of thyroid cancer cells from multiple angles, such as inhibition of viability, adhesion, motility, proliferation, migration, invasion, metastasis, angiogenesis and EMT, and promotion of apoptosis and redifferentiation.

The above conclusion principally confirms two points: 1. The expression of MMP-9 increases in various pathological processes, including thyroid cancer. 2. The inhibition of MMP-9 exhibits favorable abilities for treatment in multiple disorders, including thyroid cancer as well. These inhibitory molecules open up a new idea of therapy, and because of their high efficiency, high comprehensiveness, low toxicity, and low side effects, they possess immeasurable clinical values and application prospects after a series of clinical trials and technique improvements. We believe that with the sight into the inhibition of MMP-9, more curative natural and non-natural drugs with high inhibitory properties will be discovered, screened, and designed in the future.

Author Contributions

Writing—original draft preparation, Z.L., B.C., Y.W., S.Y., K.W. and X.M.; writing—review and editing, Z.L., J.W., B.C. and X.M. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors would like to thank the Science and Technology Developing Foundation of Jilin Province and the Beijing Cihua Medical Development Foundation for financial support.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figures and Tables

Figure 1. The multidomain structure of MMP-9. The propeptide is shown green, the active site is shown yellow, the three fibronectin repeats are shown blue, the metal binding site is shown orange, the catalytic zinc ion is shown grey, the OG domain is shown brown, and the PEX domain is shown red. Panels (A–C): structural models from 3 different studies. Panel (D): a cartoon model. (Adapted from Jennifer Vandooren et al., 2013 [1], Copyright 2013 Taylor & Francis and reproduced with permission.)

Figure 2. The mechanisms of MMP-9 inhibition in thyroid tumor cells.

Table 2

Non-natural MMP-9 inhibitors and inhibitory molecules applied to different diseases.

Reference	Molecules	Research Methods	Research Diseases	Research Subjects	Effective Dose
[16]	Theissenolactone C (LC53)	Gelatin zymographyRT-PCRWestern blotting	Glaucoma	MCP-1-stimulated THP-1 cells	2 µM, 5 µM, 10 µM
[16]	Theissenolactone C (LC53)	Gelatin zymographyRT-PCRWestern blotting	Glaucoma	IL-1β-activated primary astrocytes derived from the rat brain	2 µM, 5 µM, 10 µM
[16]	Theissenolactone C (LC53)	Gelatin zymographyRT-PCRWestern blotting	Glaucoma	An SD rat model of high intraocular pressure (IOP)-related retinal ischemia reperfusion injury	10 mg/kg
[16]	Memantine	Gelatin zymographyRT-PCRWestern blotting	Glaucoma	An SD rat model of high intraocular pressure (IOP)-related retinal ischemia reperfusion injury	20 mg/kg
[16]	Memantine	Gelatin zymographyRT-PCRWestern blotting	Glaucoma	MCP-1-stimulated THP-1 cells	100 µM
[38]	SB-3CT	Gelatin zymography	Embolic focal cerebral ischemia	A C57Bl/6 J mouse model of embolic focal cerebral ischemia	25 mg/kg
[39]	SB-3CT	Immunohistochemistry	Traumatic brain injury (TBI)	An SD rat model of traumatic brain injury induced by a fluid percussion	50 mg/kg
[40]	SB-3CT	RT-PCR	Corneal lymphangiogenesis	A C57BL/6 mouse model of inflammatory corneal neovascularization induced by corneal suture placement	50 µM, 100 µM, 200 µM
[41]	AZD1236	Gelatin zymography	Spinal cord injury	A mouse and rat model of spinal cord injury	100 mg/kg, 200 mg/kg, 300 mg/kg (oral administration)2.5 mg/mL, 5 mg/mL, 10 mg/mL (intrathecal injection)
[42]	AZD1236	/	Chronic obstructive pulmonary disease (COPD)	Patients with stable moderate-to-severe COPD	75 mg
[43]	AZ11557272	Western blotting	Smoke-induced emphysema	A Hartley strain guinea pig model exposed to the smoke or air	100 mg/kg
[44]	(Ⅰ-3,Ⅱ-3)-biacacetin	Gelatin zymography	Fibrosarcoma	HT1080 cells	10 μM
[45]	AZD3342	ELISAGelatin zymographyRT-PCR	Colonic anastomoses	An SD rat model constructed of colonic anastomoses	50 mg/kg
[46]	GM6001	ImmunohistochemistryWestern blotting	Hypertensive cerebropathy	Dahl salt-sensitive (Dahl/SS) and Lewis rat models fed with a high-salt diet	1.2 mg/kg
[47]	GM6001	Western blotting	Single severe traumatic brain injury (ssTBI)	A C57BL/6 WT mouse model of traumatic brain injury stimulated by a closed head injury	50 mg/kg
[48]	AG-L-66085	RT-PCR	Retinoblastoma (Rb)	Y79 cellsWeri-1 cells	5 μM
[49]	(R)-ND-336	Gelatin zymography	Diabetic foot ulcers (DFUs)	A db/db mouse model with a single 8-mm diameter full-thickness excisional wound	2 mg/kg
[50]	(R)-ND-336	Gelatin zymography	Diabetic foot ulcers (DFUs)	A db/db mouse model with an infected wound	10 μg
[51]	β-aminopropionitrile (BAPN)	ELISAGelatin zymographyWestern blotting	Gastric carcinoma	A nude mouse model of gastric carcinoma inoculated SGC-7901 cells	0.1 mM, 0.2 mM, 0.3 mM
[52]	Indinavir (IDV)	Gelatin zymographyRT-PCR	Cervical carcinoma (CC)	An HPV16/E2 mouse transgenic model of HR-HPV-induced estrogen-promoted CC	1.4 mg/day
[52]	Saquinavir (SQV)	Gelatin zymographyRT-PCR	Cervical carcinoma (CC)	An HPV16/E2 mouse transgenic model of HR-HPV-induced estrogen-promoted CC	1 mg/day
[52]	Lopinavir (LPV)	Gelatin zymographyRT-PCR	Cervical carcinoma (CC)	An HPV16/E2 mouse transgenic model of HR-HPV-induced estrogen-promoted CC	0.46 mg/day
[53]	Delta-tocotrienol (δT)	Gelatin zymographyRT-PCRWestern blotting	Non-small-cell lung carcinoma (NSCLC)	A549 cellsH1299 cells	10 μM, 20 μM, 30 μM
[54]	Simvastatin	Gelatin zymography	Glaucoma	Primary astrocytes derived from the human optic nerve head	5 μg/mL
[54]	Lovastatin	Gelatin zymography	Glaucoma	Primary astrocytes derived from the human optic nerve head	5 μg/mL
[54]	Atorvastatin	Gelatin zymography	Glaucoma	Primary astrocytes derived from the human optic nerve head	5 μg/mL
[55]	Lipoxin A4 methyl ester (LXA4 ME)	Western blotting	Intracerebral hemorrhage (ICH)	An SD rat model of intracerebral hemorrhage	10 ng/day, 100 ng/day
[56]	Hydroxytyrosol (HT)	ELISAGelatin zymographyRT-PCR	Atherosclerosis (AS)	PBMCsU937 cells	1–10 μMIC50 = 10 μM
[57]	Walnut-derived peptide TWLPLPR (TW-7)	Immunohistochemistry	Alzheimer’s disease (AD)	β-amyloid 25–35-injured bEnd.3 cells	100 μM
[58]	Thiamine	ELISA	Sepsis	86 blood samples of septic patients	200 mg
[58]	Ascorbic acid	ELISA	Sepsis	86 blood samples of septic patients	50 mg/kg
[59]	MK2206 2HCl	ImmunohistochemistryRT-PCRWestern blotting	Oral squamous cell carcinoma (OSCC)	CAL27 cellsSCC25 cells	6 μM, 10 μM
[60]	U0126	Gelatin zymographyRT-PCR	Diabetic retinopathy (DR)	An SD rate model of diabetes induced by streptozotocin	0.1 mM
[61]	BB-94 (Batimastat)	Gelatin zymographyRT-PCR	Acute kidney allograft rejection	A Lewis rat model of orthotopic kidney allotransplantation	30 mg/kg
[62]	Doxycycline	Gelatin zymography	Skeletal muscle ischemia-reperfusion injury	An SD rat model of skeletal muscle ischemia-reperfusion injury	50 mg/kg, 200 mg/kg
[63]	Melatonin	Gelatin zymographyWestern blotting	Transient focal cerebral ischemia	A C57BL/B6 mouse model of transient focal cerebral ischemia	5 mg/kg
[64]	1, 25(OH)2D3	ELISA	Pulmonary tuberculosis (PTB)	Peripheral blood mononuclear cells (PBMCs) from 43 PTB patients	0.1 μM
[65]	Imidaprilat	Gelatin zymography	Atherosclerosis	THP-1 cells	100 nM, 1000 nM

Table 5

The signaling pathways in thyroid carcinoma, including MMP-9.

Reference	Type of Thyroid Carcinoma	Signaling Pathways
[107]	PTC	TR4/circ-FNLA/miR-149-5p/MMP-9
[108]	PTC	SOX12/POU2F1, POU3F1/MMP-9
[109]	PTC	DUXAP10/Akt/mTOR/MMP-9
[110]	PTC	KDM1A/TIMP-1/MMP-9
[111]	PTC	ALOX5/ MMP9
[112]	PTC	ROCK1/MMP-9
[113]	FTC	FRNK/FAK/EGF/MMP-9
[114]	FTC	S1P/S1P1/MMP-9
[115]	ATC	PLK1/MMP-9
[116]	ATC	S1P/S1P2/MMP-9
[117]	PTC, FTC	S100A4/MMP-9
[118]	PTC, ATC	Enigma/PI3K/AKT/MMP-9
[119]	PTC, FTC, ATC	IL-17RB/ERK1/2/MMP-9

Table 6

MMP-9 inhibitors and inhibitory molecules applied to thyroid carcinoma.

Reference	Molecules	Research Methods	Type of Thyroid Carcinoma	Research Models	Doses	Results
[122]	Curcumin	Gelatin zymographyWestern blotting	PTC	K1 cells	12.5 μM, 25 μM, 50 μM	Migration inhibitionMetastasis inhibitionEMT inhibitionViability inhibition
[123]	Curcumin	Gelatin zymography	PTC	K1 cells	25 μM, 50 μM	Migration inhibition
[124]	Curcumin	Western blotting	PTC	TPC-1 cells	23.31 μM	Migration inhibitionInvasion inhibitionEMT inhibitionViability inhibition
[125]	Evodiamine	Western blotting	PTC	TPC-1 cells	5 μM	Proliferation inhibitionMigration inhibitionEMT inhibitionViability inhibition
[125]	Evodiamine	Western blotting	ATC	SW1736 cells	5 μM	Proliferation inhibitionMigration inhibitionEMT inhibitionViability inhibition
[126]	Schizandrin A (SchA)	RT-PCRWestern blotting	PTC	TPC-1 cells	50 µM	Proliferation inhibitionMigration inhibitionInvasion inhibition
[127]	Emodin	Western blotting	ATC	8505C cellsSW1736 cells	10 µM, 15 µM, 20 µM, 25 µM	Proliferation inhibitionMetastasis inhibitionAngiogenesis inhibition
[128]	Ginsenoside Rg3	Western blotting	PTC	TPC-1 cellsBCPAP cells	50 µM, 100 µM	Metastasis inhibition
[128]	Ginsenoside Rg3	Western blotting	ATC	C643 cellsOcut-2c cells	50 µM, 100 µM	Metastasis inhibition
[129]	Taraxasterol (TAR)	Western blotting	PTC	TPC-1 cellsBCPAP cells	2.5 µg/mL, 5 µg/mL, 10 µg/mL	Migration inhibitionInvasion inhibitionEMT inhibition
[130]	Epigallocatechin-3-gallate (EGCG)	Gelatin zymographyWestern blotting	PTC	FB-2 cells	10 μM, 40 μM, 60 μM	Proliferation inhibitionEMT inhibitionMotility inhibition
[131]	Diindolylmethane (DIM)	Gelatin zymographyWestern blotting	PTC	BCPAP cells	25 µM	Proliferation inhibitionMigration inhibitionInvasion inhibitionMetastasis inhibitionAdhesion inhibition
[131]	Diindolylmethane (DIM)	Gelatin zymographyWestern blotting	ATC	8505C cells	25 µM	Proliferation inhibitionMigration inhibitionInvasion inhibitionMetastasis inhibitionAdhesion inhibition
[131]	Diindolylmethane (DIM)	Gelatin zymographyWestern blotting	FTC	CGTHW-1 cellsML-1 cells	25 µM	Proliferation inhibitionMigration inhibitionInvasion inhibitionMetastasis inhibitionAdhesion inhibition
[132]	Salidroside	RT-PCRWestern blotting	ATC	WRO cells	10 µM, 20 µM, 40 µM	Migration inhibitionInvasion inhibition
[133]	Quercetin	RT-PCR	PTC	BCPAP cells	100 μM	Migration inhibitionInvasion inhibitionAdhesion inhibitionApoptosis promotion
[134]	Silibinin	Gelatin zymographyRT-PCR	PTC	TPC-1 cells	50 µM	Migration inhibition
[135]	Sevoflurane	Western blotting	PTC	TPC-1 cellsIHH-4 cells	2.5%	Migration inhibitionInvasion inhibitionViability inhibitionApoptosis promotion
[136]	Fingolimod (FTY720)	Gelatin zymographyWestern blotting	FTC	ML-1 cells	10 μM	Proliferation inhibitionInvasion inhibition
[137]	Valproic Acid (VPA)	RT-PCR	ATC	8305C cells	0.1 mM, 1 mM, 5 mM	Redifferentiation promotion
[137]	Valproic Acid (VPA)	RT-PCR	PTC	BCPAP cells	0.1 mM, 1 mM	Redifferentiation promotion
[138]	BMAP-28	ColorimetryRT-PCR	MTC	TT cells	4 µM	Proliferation inhibition
[139]	1α,25(OH)2D3	Gelatin zymographyWestern blotting	ATC	8505C cells	0.1 µM	Migration inhibitionInvasion inhibition
[139]	MART-10	Gelatin zymographyWestern blotting	ATC	8505C cells	0.1 µM	Migration inhibitionInvasion inhibition
[140]	Gemigliptin and metformin	Western blotting	PTC	TPC-1 cells	1 mM Gemigliptin and 30 mM metformin	Proliferation inhibitionMigration inhibitionViability inhibition

EMT: epithelial-mesenchymal transition.

References

1. Vandooren, J.; Van den Steen, P.E.; Opdenakker, G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): The next decade. Crit. Rev. Biochem. Mol. Biol.; 2013; 48, pp. 222-272. [DOI: https://dx.doi.org/10.3109/10409238.2013.770819] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23547785]

2. Wang, J.; Shi, Q.; Yuan, T.X.; Song, Q.L.; Zhang, Y.; Wei, Q.; Zhou, L.; Luo, J.; Zuo, G.; Tang, M. et al. Matrix metalloproteinase 9 (MMP-9) in osteosarcoma: Review and meta-analysis. Clin. Chim. Acta; 2014; 433, pp. 225-231. [DOI: https://dx.doi.org/10.1016/j.cca.2014.03.023] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24704305]

3. Huang, H. Matrix Metalloproteinase-9 (MMP-9) as a Cancer Biomarker and MMP-9 Biosensors: Recent Advances. Sensors; 2018; 18, 3249. [DOI: https://dx.doi.org/10.3390/s18103249]

4. Atkinson, J.J.; Senior, R.M. Matrix metalloproteinase-9 in lung remodeling. Am. J. Respir. Cell Mol. Biol.; 2003; 28, pp. 12-24. [DOI: https://dx.doi.org/10.1165/rcmb.2002-0166TR] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12495928]

5. Muroski, M.E.; Roycik, M.D.; Newcomer, R.G.; Van den Steen, P.E.; Opdenakker, G.; Monroe, H.R.; Sahab, Z.J.; Sang, Q.X. Matrix metalloproteinase-9/gelatinase B is a putative therapeutic target of chronic obstructive pulmonary disease and multiple sclerosis. Curr. Pharm. Biotechnol.; 2008; 9, pp. 34-46.

6. Deleon-Pennell, K.Y.; Altara, R.; Yabluchanskiy, A.; Modesti, A.; Lindsey, M.L. The circular relationship between matrix metalloproteinase-9 and inflammation following myocardial infarction. IUBMB Life; 2015; 67, pp. 611-618. [DOI: https://dx.doi.org/10.1002/iub.1408]

7. Yabluchanskiy, A.; Ma, Y.; Iyer, R.P.; Hall, M.E.; Lindsey, M.L. Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. Physiology; 2013; 28, pp. 391-403. [DOI: https://dx.doi.org/10.1152/physiol.00029.2013]

8. Wang, L.; Wei, C.; Deng, L.; Wang, Z.; Song, M.; Xiong, Y.; Liu, M. The Accuracy of Serum Matrix Metalloproteinase-9 for Predicting Hemorrhagic Transformation After Acute Ischemic Stroke: A Systematic Review and Meta-Analysis. J. Stroke Cerebrovasc. Dis.; 2018; 27, pp. 1653-1665. [DOI: https://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.01.023]

9. Ramos-Fernandez, M.; Bellolio, M.F.; Stead, L.G. Matrix metalloproteinase-9 as a marker for acute ischemic stroke: A systematic review. J. Stroke Cerebrovasc. Dis.; 2011; 20, pp. 47-54. [DOI: https://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2009.10.008]

10. Bronisz, E.; Kurkowska-Jastrzebska, I. Matrix Metalloproteinase 9 in Epilepsy: The Role of Neuroinflammation in Seizure Development. Mediat. Inflamm.; 2016; 2016, 7369020. [DOI: https://dx.doi.org/10.1155/2016/7369020]

11. Li, H.; Sheng, Z.; Khan, S.; Zhang, R.; Liu, Y.; Zhang, Y.; Yong, V.W.; Xue, M. Matrix Metalloproteinase-9 as an Important Contributor to the Pathophysiology of Depression. Front. Neurol.; 2022; 13, 861843. [DOI: https://dx.doi.org/10.3389/fneur.2022.861843] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35370878]

12. Shoari, A.; Kanavi, M.R.; Rasaee, M.J. Inhibition of matrix metalloproteinase-9 for the treatment of dry eye syndrome; a review study. Exp. Eye Res.; 2021; 205, 108523. [DOI: https://dx.doi.org/10.1016/j.exer.2021.108523] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33662353]

13. Ram, M.; Sherer, Y.; Shoenfeld, Y. Matrix Metalloproteinase-9 and Autoimmune Diseases. J. Clin. Immunol.; 2006; 26, pp. 299-307. [DOI: https://dx.doi.org/10.1007/s10875-006-9022-6]

14. Mondal, S.; Adhikari, N.; Banerjee, S.; Amin, S.A.; Jha, T. Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: A minireview. Eur. J. Med. Chem.; 2020; 194, 112260. [DOI: https://dx.doi.org/10.1016/j.ejmech.2020.112260] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32224379]

15. Mohajeri, M.; Bianconi, V.; Avila-Rodriguez, M.F.; Barreto, G.E.; Jamialahmadi, T.; Pirro, M.; Sahebkar, A. Curcumin: A phytochemical modulator of estrogens and androgens in tumors of the reproductive system. Pharmacol. Res.; 2020; 156, 104765. [DOI: https://dx.doi.org/10.1016/j.phrs.2020.104765] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32217147]

16. Lin, F.L.; Cheng, Y.W.; Yu, M.; Ho, J.D.; Kuo, Y.C.; Chiou, G.C.Y.; Chang, H.M.; Lee, T.H.; Hsiao, G. The fungus-derived retinoprotectant theissenolactone C improves glaucoma-like injury mediated by MMP-9 inhibition. Phytomedicine; 2019; 56, pp. 207-214. [DOI: https://dx.doi.org/10.1016/j.phymed.2018.11.002]

17. Tohge, T.; Fernie, A.R. Leveraging Natural Variance towards Enhanced Understanding of Phytochemical Sunscreens. Trends Plant Sci.; 2017; 22, pp. 308-315. [DOI: https://dx.doi.org/10.1016/j.tplants.2017.01.003]

18. Yiemwattana, I.; Kaomongkolgit, R.; Wirojchanasak, S.; Chaisomboon, N. Morus alba Stem Extract Suppresses Matrix Metalloproteinases (MMP)-1, MMP-9, and Tissue Inhibitors of Metalloproteinase (TIMP)-1 Expression via Inhibition of IkappaBalpha Degradation Induced by Porphyromonas gingivalis LPS Signal in THP-1 Cells. Eur. J. Dent.; 2019; 13, pp. 229-234. [DOI: https://dx.doi.org/10.1055/s-0039-1694314]

19. Subedi, L.; Gaire, B.P. Tanshinone IIA: A phytochemical as a promising drug candidate for neurodegenerative diseases. Pharmacol. Res.; 2021; 169, 105661. [DOI: https://dx.doi.org/10.1016/j.phrs.2021.105661]

20. Lagoa, R.; Silva, J.; Rodrigues, J.R.; Bishayee, A. Advances in phytochemical delivery systems for improved anticancer activity. Biotechnol. Adv.; 2020; 38, 107382. [DOI: https://dx.doi.org/10.1016/j.biotechadv.2019.04.004]

21. Jimenez-Sanchez, C.; Lozano-Sanchez, J.; Segura-Carretero, A.; Fernandez-Gutierrez, A. Alternatives to conventional thermal treatments in fruit-juice processing. Part 2: Effect on composition, phytochemical content, and physicochemical, rheological, and organoleptic properties of fruit juices. Crit. Rev. Food Sci. Nutr.; 2017; 57, pp. 637-652. [DOI: https://dx.doi.org/10.1080/10408398.2014.914019]

22. Chen, X.; Li, H.; Zhang, B.; Deng, Z. The synergistic and antagonistic antioxidant interactions of dietary phytochemical combinations. Crit. Rev. Food Sci. Nutr.; 2022; 62, pp. 5658-5677. [DOI: https://dx.doi.org/10.1080/10408398.2021.1888693]

23. Sarkar, J.; Nandy, S.K.; Chowdhury, A.; Chakraborti, T.; Chakraborti, S. Inhibition of MMP-9 by green tea catechins and prediction of their interaction by molecular docking analysis. Biomed. Pharmacother.; 2016; 84, pp. 340-347. [DOI: https://dx.doi.org/10.1016/j.biopha.2016.09.049]

24. Fang, C.Y.; Wu, C.C.; Hsu, H.Y.; Chuang, H.Y.; Huang, S.Y.; Tsai, C.H.; Chang, Y.; Tsao, G.S.; Chen, C.L.; Chen, J.Y. EGCG inhibits proliferation, invasiveness and tumor growth by up-regulation of adhesion molecules, suppression of gelatinases activity, and induction of apoptosis in nasopharyngeal carcinoma cells. Int. J. Mol. Sci.; 2015; 16, pp. 2530-2558. [DOI: https://dx.doi.org/10.3390/ijms16022530] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25625511]

25. Annabi, B.; Currie, J.C.; Moghrabi, A.; Beliveau, R. Inhibition of HuR and MMP-9 expression in macrophage-differentiated HL-60 myeloid leukemia cells by green tea polyphenol EGCg. Leuk. Res.; 2007; 31, pp. 1277-1284. [DOI: https://dx.doi.org/10.1016/j.leukres.2006.10.001]

26. Park, J.W.; Jang, Y.H.; Kim, J.M.; Lee, H.; Park, W.K.; Lim, M.B.; Chu, Y.K.; Lo, E.H.; Lee, S.R. Green tea polyphenol (-)-epigallocatechin gallate reduces neuronal cell damage and up-regulation of MMP-9 activity in hippocampal CA1 and CA2 areas following transient global cerebral ischemia. J. Neurosci. Res.; 2009; 87, pp. 567-575. [DOI: https://dx.doi.org/10.1002/jnr.21847]

27. Jung, J.S.; Jung, K.; Kim, D.H.; Kim, H.S. Selective inhibition of MMP-9 gene expression by mangiferin in PMA-stimulated human astroglioma cells: Involvement of PI3K/Akt and MAPK signaling pathways. Pharmacol. Res.; 2012; 66, pp. 95-103. [DOI: https://dx.doi.org/10.1016/j.phrs.2012.02.013] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22465218]

28. Dilshara, M.G.; Kang, C.H.; Choi, Y.H.; Kim, G.Y. Mangiferin inhibits tumor necrosis factor-alpha-induced matrix metalloproteinase-9 expression and cellular invasion by suppressing nuclear factor-kappaB activity. BMB Rep.; 2015; 48, pp. 559-564. [DOI: https://dx.doi.org/10.5483/BMBRep.2015.48.10.003] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25739392]

29. Xiao, J.; Liu, L.; Zhong, Z.; Xiao, C.; Zhang, J. Mangiferin regulates proliferation and apoptosis in glioma cells by induction of microRNA-15b and inhibition of MMP-9 expression. Oncol. Rep.; 2015; 33, pp. 2815-2820. [DOI: https://dx.doi.org/10.3892/or.2015.3919]

30. Li, H.; Huang, J.; Yang, B.; Xiang, T.; Yin, X.; Peng, W.; Cheng, W.; Wan, J.; Luo, F.; Li, H. et al. Mangiferin exerts antitumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and beta-catenin signaling pathway. Toxicol. Appl. Pharmacol.; 2013; 272, pp. 180-190. [DOI: https://dx.doi.org/10.1016/j.taap.2013.05.011] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23707762]

31. Shen, C.Y.; Lee, C.F.; Chou, W.T.; Hwang, J.J.; Tyan, Y.S.; Chuang, H.Y. Liposomal beta-Sitosterol Suppresses Metastasis of CT26/luc Colon Carcinoma via Inhibition of MMP-9 and Evoke of Immune System. Pharmaceutics; 2022; 14, 1214. [DOI: https://dx.doi.org/10.3390/pharmaceutics14061214]

32. Shamseddin, A.; Crauste, C.; Durand, E.; Villeneuve, P.; Dubois, G.; Pavlickova, T.; Durand, T.; Vercauteren, J.; Veas, F. Resveratrol-Linoleate protects from exacerbated endothelial permeability via a drastic inhibition of the MMP-9 activity. Biosci. Rep.; 2018; 38, BSR20171712. [DOI: https://dx.doi.org/10.1042/BSR20171712]

33. Zhang, W.; Song, J.-K.; Zhang, X.; Zhou, Q.-M.; He, G.-R.; Xu, X.-N.; Rong, Y.; Zhou, W.-X.; Du, G.-H. Salvianolic acid A attenuates ischemia reperfusion induced rat brain damage by protecting the blood brain barrier through MMP-9 inhibition and anti-inflammation. Chin. J. Nat. Med.; 2018; 16, pp. 184-193. [DOI: https://dx.doi.org/10.1016/S1875-5364(18)30046-3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29576054]

34. Wu, Y.H.; Kuraji, R.; Taya, Y.; Ito, H.; Numabe, Y. Effects of theaflavins on tissue inflammation and bone resorption on experimental periodontitis in rats. J. Periodontal Res.; 2018; 53, pp. 1009-1019. [DOI: https://dx.doi.org/10.1111/jre.12600]

35. Cao, J.; Ye, B.; Lin, L.; Tian, L.; Yang, H.; Wang, C.; Huang, W.; Huang, Z. Curcumin Alleviates oxLDL Induced MMP-9 and EMMPRIN Expression through the Inhibition of NF-kappaB and MAPK Pathways in Macrophages. Front. Pharmacol.; 2017; 8, 62. [DOI: https://dx.doi.org/10.3389/fphar.2017.00062] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28261097]

36. Shi, H.; Liu, L.; Liu, L.M.; Geng, J.; Chen, L. Inhibition of tumor growth by beta-elemene through downregulation of the expression of uPA, uPAR, MMP-2, and MMP-9 in a murine intraocular melanoma model. Melanoma Res.; 2015; 25, pp. 15-21. [DOI: https://dx.doi.org/10.1097/CMR.0000000000000124] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25405459]

37. Kim, M.H.; Lee, H.; Yang, W.M. Angelica gigas ameliorates the destruction of gingival tissues via inhibition of MMP-9 activity. RSC Adv.; 2018; 8, pp. 13089-13093. [DOI: https://dx.doi.org/10.1039/C7RA12531C]

38. Cui, J.; Chen, S.; Zhang, C.; Meng, F.; Wu, W.; Hu, R.; Hadass, O.; Lehmidi, T.; Blair, G.J.; Lee, M. et al. Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia. Mol. Neurodegener.; 2012; 7, 21. [DOI: https://dx.doi.org/10.1186/1750-1326-7-21]

39. Jia, F.; Yin, Y.H.; Gao, G.Y.; Wang, Y.; Cen, L.; Jiang, J.Y. MMP-9 inhibitor SB-3CT attenuates behavioral impairments and hippocampal loss after traumatic brain injury in rat. J. Neurotrauma; 2014; 31, pp. 1225-1234. [DOI: https://dx.doi.org/10.1089/neu.2013.3230]

40. Du, H.T.; Du, L.L.; Tang, X.L.; Ge, H.Y.; Liu, P. Blockade of MMP-2 and MMP-9 inhibits corneal lymphangiogenesis. Graefe’s Arch. Clin. Exp. Ophthalmol.; 2017; 255, pp. 1573-1579. [DOI: https://dx.doi.org/10.1007/s00417-017-3651-8]

41. Ahmed, Z.; Alhajlah, S.; Thompson, A.M.; Fairclough, R.J. Clinic-ready inhibitor of MMP-9/-12 restores sensory and functional decline in rodent models of spinal cord injury. Clin. Transl. Med.; 2022; 12, e884. [DOI: https://dx.doi.org/10.1002/ctm2.884] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35593139]

42. Dahl, R.; Titlestad, I.; Lindqvist, A.; Wielders, P.; Wray, H.; Wang, M.; Samuelsson, V.; Mo, J.; Holt, A. Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: A randomised controlled trial. Pulm. Pharmacol. Ther.; 2012; 25, pp. 169-177. [DOI: https://dx.doi.org/10.1016/j.pupt.2011.12.011]

43. Churg, A.; Wang, R.; Wang, X.; Onnervik, P.O.; Thim, K.; Wright, J.L. Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs. Thorax; 2007; 62, pp. 706-713. [DOI: https://dx.doi.org/10.1136/thx.2006.068353]

44. Nanjan, P.; Nambiar, J.; Nair, B.G.; Banerji, A. Synthesis and discovery of (I-3, II-3)-biacacetin as a novel non-zinc binding inhibitor of MMP-2 and MMP-9. Bioorg. Med. Chem.; 2015; 23, pp. 3781-3787. [DOI: https://dx.doi.org/10.1016/j.bmc.2015.03.084]

45. Krarup, P.M.; Eld, M.; Heinemeier, K.; Jorgensen, L.N.; Hansen, M.B.; Agren, M.S. Expression and inhibition of matrix metalloproteinase (MMP)-8, MMP-9 and MMP-12 in early colonic anastomotic repair. Int. J. Color. Dis.; 2013; 28, pp. 1151-1159. [DOI: https://dx.doi.org/10.1007/s00384-013-1697-6]

46. Kalani, A.; Pushpakumar, S.B.; Vacek, J.C.; Tyagi, S.C.; Tyagi, N. Inhibition of MMP-9 attenuates hypertensive cerebrovascular dysfunction in Dahl salt-sensitive rats. Mol. Cell. Biochem.; 2016; 413, pp. 25-35. [DOI: https://dx.doi.org/10.1007/s11010-015-2623-8]

47. Lin, C.; Wu, W.; Lu, H.; Li, W.; Bao, Z.; Wang, Y.; Zhao, L.; Guo, T.; Cai, N.; Li, Z. et al. MMP-9 Inhibitor GM6001 Prevents the Development of ssTBI-Induced Parkinson’s Disease via the Autophagy Pathway. Cell. Mol. Neurobiol.; 2021; 41, pp. 1651-1663. [DOI: https://dx.doi.org/10.1007/s10571-020-00933-z] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32770297]

48. Webb, A.H.; Gao, B.T.; Goldsmith, Z.K.; Irvine, A.S.; Saleh, N.; Lee, R.P.; Lendermon, J.B.; Bheemreddy, R.; Zhang, Q.; Brennan, R.C. et al. Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma. BMC Cancer; 2017; 17, 434. [DOI: https://dx.doi.org/10.1186/s12885-017-3418-y]

49. Nguyen, T.T.; Ding, D.; Wolter, W.R.; Perez, R.L.; Champion, M.M.; Mahasenan, K.V.; Hesek, D.; Lee, M.; Schroeder, V.A.; Jones, J.I. et al. Validation of Matrix Metalloproteinase-9 (MMP-9) as a Novel Target for Treatment of Diabetic Foot Ulcers in Humans and Discovery of a Potent and Selective Small-Molecule MMP-9 Inhibitor That Accelerates Healing. J. Med. Chem.; 2018; 61, pp. 8825-8837. [DOI: https://dx.doi.org/10.1021/acs.jmedchem.8b01005] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30212201]

50. Peng, Z.; Nguyen, T.T.; Song, W.; Anderson, B.; Wolter, W.R.; Schroeder, V.A.; Hesek, D.; Lee, M.; Mobashery, S.; Chang, M. Selective MMP-9 Inhibitor (R)-ND-336 Alone or in Combination with Linezolid Accelerates Wound Healing in Infected Diabetic Mice. ACS Pharmacol. Transl. Sci.; 2021; 4, pp. 107-117. [DOI: https://dx.doi.org/10.1021/acsptsci.0c00104]

51. Zhao, L.; Niu, H.; Liu, Y.; Wang, L.; Zhang, N.; Zhang, G.; Liu, R.; Han, M. LOX inhibition downregulates MMP-2 and MMP-9 in gastric cancer tissues and cells. J. Cancer; 2019; 10, pp. 6481-6490. [DOI: https://dx.doi.org/10.7150/jca.33223] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31777578]

52. Qiu, Y.; Maione, F.; Capano, S.; Meda, C.; Picconi, O.; Brundu, S.; Pisacane, A.; Sapino, A.; Palladino, C.; Barillari, G. et al. HIV Protease Inhibitors Block HPV16-Induced Murine Cervical Carcinoma and Promote Vessel Normalization in Association with MMP-9 Inhibition and TIMP-3 Induction. Mol. Cancer Ther.; 2020; 19, pp. 2476-2489. [DOI: https://dx.doi.org/10.1158/1535-7163.MCT-20-0055]

53. Rajasinghe, L.D.; Pindiprolu, R.H.; Gupta, S.V. Delta-tocotrienol inhibits non-small-cell lung cancer cell invasion via the inhibition of NF-kappaB, uPA activator, and MMP-9. OncoTargets Ther.; 2018; 11, pp. 4301-4314. [DOI: https://dx.doi.org/10.2147/OTT.S160163] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30100736]

54. Kim, M.L.; Sung, K.R.; Kwon, J.; Shin, J.A. Statins Suppress TGF-beta2-Mediated MMP-2 and MMP-9 Expression and Activation Through RhoA/ROCK Inhibition in Astrocytes of the Human Optic Nerve Head. Invest. Ophthalmol. Vis. Sci.; 2020; 61, 29. [DOI: https://dx.doi.org/10.1167/iovs.61.5.29]

55. Song, Y.; Yang, Y.; Cui, Y.; Gao, J.; Wang, K.; Cui, J. Lipoxin A4 Methyl Ester Reduces Early Brain Injury by Inhibition of the Nuclear Factor Kappa B (NF-kappaB)-Dependent Matrix Metallopeptidase 9 (MMP-9) Pathway in a Rat Model of Intracerebral Hemorrhage. Med. Sci. Monit.; 2019; 25, pp. 1838-1847. [DOI: https://dx.doi.org/10.12659/MSM.915119]

56. Scoditti, E.; Nestola, A.; Massaro, M.; Calabriso, N.; Storelli, C.; De Caterina, R.; Carluccio, M.A. Hydroxytyrosol suppresses MMP-9 and COX-2 activity and expression in activated human monocytes via PKCalpha and PKCbeta1 inhibition. Atherosclerosis; 2014; 232, pp. 17-24. [DOI: https://dx.doi.org/10.1016/j.atherosclerosis.2013.10.017]

57. Dang, Q.; Wu, D.; Li, Y.; Fang, L.; Liu, C.; Wang, X.; Liu, X.; Min, W. Walnut-derived peptides ameliorate d-galactose-induced memory impairments in a mouse model via inhibition of MMP-9-mediated blood-brain barrier disruption. Food Res. Int.; 2022; 162, 112029. [DOI: https://dx.doi.org/10.1016/j.foodres.2022.112029] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36461249]

58. Lubis, B.; Lelo, A.; Amelia, P.; Prima, A. The Effect of Thiamine, Ascorbic Acid, and the Combination of Them on the Levels of Matrix Metalloproteinase-9 (MMP-9) and Tissue Inhibitor of Matrix Metalloproteinase-1 (TIMP-1) in Sepsis Patients. Infect. Drug Resist.; 2022; 15, pp. 5741-5751. [DOI: https://dx.doi.org/10.2147/IDR.S378523]

59. Yin, P.; Chen, J.; Wu, Y.; Gao, F.; Wen, J.; Zhang, W.; Su, Y.; Zhang, X. Chemoprevention of 4NQO-Induced Mouse Tongue Carcinogenesis by AKT Inhibitor through the MMP-9/RhoC Signaling Pathway and Autophagy. Anal. Cell. Pathol.; 2022; 2022, 3770715. [DOI: https://dx.doi.org/10.1155/2022/3770715] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36247874]

60. Mohammad, G.; Mairaj Siddiquei, M.; Imtiaz Nawaz, M.; Abu El-Asrar, A.M. The ERK1/2 Inhibitor U0126 Attenuates Diabetes-Induced Upregulation of MMP-9 and Biomarkers of Inflammation in the Retina. J. Diabetes Res.; 2013; 2013, 658548. [DOI: https://dx.doi.org/10.1155/2013/658548]

61. Ermolli, M.; Schumacher, M.; Lods, N.; Hammoud, M.; Marti, H.P. Differential expression of MMP-2/MMP-9 and potential benefit of an MMP inhibitor in experimental acute kidney allograft rejection. Transpl. Immunol.; 2003; 11, pp. 137-145. [DOI: https://dx.doi.org/10.1016/S0966-3274(02)00150-8]

62. Roach, D.M.; Fitridge, R.A.; Laws, P.E.; Millard, S.H.; Varelias, A.; Cowled, P.A. Up-regulation of MMP-2 and MMP-9 leads to degradation of type IV collagen during skeletal muscle reperfusion injury; protection by the MMP inhibitor, doxycycline. Eur. J. Vasc. Endovasc. Surg.; 2002; 23, pp. 260-269. [DOI: https://dx.doi.org/10.1053/ejvs.2002.1598]

63. Tai, S.H.; Chen, H.Y.; Lee, E.J.; Chen, T.Y.; Lin, H.W.; Hung, Y.C.; Huang, S.Y.; Chen, Y.H.; Lee, W.T.; Wu, T.S. Melatonin inhibits postischemic matrix metalloproteinase-9 (MMP-9) activation via dual modulation of plasminogen/plasmin system and endogenous MMP inhibitor in mice subjected to transient focal cerebral ischemia. J. Pineal Res.; 2010; 49, pp. 332-341. [DOI: https://dx.doi.org/10.1111/j.1600-079X.2010.00797.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20663046]

64. Anand, S.P.; Selvaraj, P. Effect of 1, 25 dihydroxyvitamin D(3) on matrix metalloproteinases MMP-7, MMP-9 and the inhibitor TIMP-1 in pulmonary tuberculosis. Clin. Immunol.; 2009; 133, pp. 126-131. [DOI: https://dx.doi.org/10.1016/j.clim.2009.06.009] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19615945]

65. Kojima, C.; Ino, J.; Ishii, H.; Nitta, K.; Yoshida, M. MMP-9 inhibition by ACE inhibitor reduces oxidized LDL-mediated foam-cell formation. J. Atheroscler. Thromb.; 2010; 17, pp. 97-105. [DOI: https://dx.doi.org/10.5551/jat.1685] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20093780]

66. Ye, Y.; Kuang, X.; Xie, Z.; Liang, L.; Zhang, Z.; Zhang, Y.; Ma, F.; Gao, Q.; Chang, R.; Lee, H.H. et al. Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1. Genome Med.; 2020; 12, 83. [DOI: https://dx.doi.org/10.1186/s13073-020-00780-z]

67. Lee, M.; Chen, Z.; Tomlinson, B.N.; Gooyit, M.; Hesek, D.; Juarez, M.R.; Nizam, R.; Boggess, B.; Lastochkin, E.; Schroeder, V.A. et al. Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury. ACS Chem. Neurosci.; 2015; 6, pp. 1658-1664. [DOI: https://dx.doi.org/10.1021/acschemneuro.5b00140]

68. Magnussen, H.; Watz, H.; Kirsten, A.; Wang, M.; Wray, H.; Samuelsson, V.; Mo, J.; Kay, R. Safety and tolerability of an oral MMP-9 and -12 inhibitor, AZD1236, in patients with moderate-to-severe COPD: A randomised controlled 6-week trial. Pulm. Pharmacol. Ther.; 2011; 24, pp. 563-570. [DOI: https://dx.doi.org/10.1016/j.pupt.2011.05.003]

69. Kwan, M.Y.; Choo, A.; Hanania, T.; Ghavami, A.; Beltran, J.; Shea, J.; Barboza, A.; Hu, A.; Fowler, M.; Neelagiri, V.R. et al. Biomarker Analysis of Orally Dosed, Dual Active, Matrix Metalloproteinase (MMP)-2 and MMP-9 Inhibitor, AQU-118, in the Spinal Nerve Ligation (SNL) Rat Model of Neuropathic Pain. Int. J. Mol. Sci.; 2019; 20, 811. [DOI: https://dx.doi.org/10.3390/ijms20040811]

70. Shirian, J.; Arkadash, V.; Cohen, I.; Sapir, T.; Radisky, E.S.; Papo, N.; Shifman, J.M. Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14. FEBS Lett.; 2018; 592, pp. 1122-1134. [DOI: https://dx.doi.org/10.1002/1873-3468.13016]

71. Scannevin, R.H.; Alexander, R.; Haarlander, T.M.; Burke, S.L.; Singer, M.; Huo, C.; Zhang, Y.M.; Maguire, D.; Spurlino, J.; Deckman, I. et al. Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation. J. Biol. Chem.; 2017; 292, pp. 17963-17974. [DOI: https://dx.doi.org/10.1074/jbc.M117.806075] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28860188]

72. Mogharrabi, M.; Rahimi, H.R.; Hasanzadeh, S.; Dastani, M.; Kazemi-Oskuee, R.; Akhlaghi, S.; Soukhtanloo, M. The effects of nanomicelle of curcumin on the matrix metalloproteinase (MMP-2, 9) activity and expression in patients with coronary artery disease (CAD): A randomized controlled clinical trial. ARYA Atheroscler.; 2020; 16, pp. 136-145.

73. Sandborn, W.J.; Bhandari, B.R.; Fogel, R.; Onken, J.; Yen, E.; Zhao, X.; Jiang, Z.; Ge, D.; Xin, Y.; Ye, Z. et al. Randomised clinical trial: A phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis. Aliment. Pharmacol. Ther.; 2016; 44, pp. 157-169. [DOI: https://dx.doi.org/10.1111/apt.13653]

74. Rudek, M.A.; Figg, W.D.; Dyer, V.; Dahut, W.; Turner, M.L.; Steinberg, S.M.; Liewehr, D.J.; Kohler, D.R.; Pluda, J.M.; Reed, E. Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer. J. Clin. Oncol.; 2001; 19, pp. 584-592. [DOI: https://dx.doi.org/10.1200/JCO.2001.19.2.584] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11208854]

75. Shah, M.A.; Cunningham, D.; Metges, J.P.; Van Cutsem, E.; Wainberg, Z.; Elboudwarej, E.; Lin, K.W.; Turner, S.; Zavodovskaya, M.; Inzunza, D. et al. Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival. J. Immunother. Cancer; 2021; 9, e003580. [DOI: https://dx.doi.org/10.1136/jitc-2021-003580]

76. Deng, Y.; Li, H.; Wang, M.; Li, N.; Tian, T.; Wu, Y.; Xu, P.; Yang, S.; Zhai, Z.; Zhou, L. et al. Global Burden of Thyroid Cancer From 1990 to 2017. JAMA Netw. Open; 2020; 3, e208759. [DOI: https://dx.doi.org/10.1001/jamanetworkopen.2020.8759]

77. Cabanillas, M.E.; McFadden, D.G.; Durante, C. Thyroid cancer. Lancet; 2016; 388, pp. 2783-2795. [DOI: https://dx.doi.org/10.1016/S0140-6736(16)30172-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27240885]

78. Miranda-Filho, A.; Lortet-Tieulent, J.; Bray, F.; Cao, B.; Franceschi, S.; Vaccarella, S.; Dal Maso, L. Thyroid cancer incidence trends by histology in 25 countries: A population-based study. Lancet Diabetes Endocrinol.; 2021; 9, pp. 225-234. [DOI: https://dx.doi.org/10.1016/S2213-8587(21)00027-9]

79. Todsen, T.; Bennedbaek, F.N.; Kiss, K.; Hegedus, L. Ultrasound-guided fine-needle aspiration biopsy of thyroid nodules. Head Neck; 2021; 43, pp. 1009-1013. [DOI: https://dx.doi.org/10.1002/hed.26598]

80. Son, J.I.; Rhee, S.Y.; Woo, J.T.; Park, W.S.; Byun, J.K.; Kim, Y.J.; Byun, J.M.; Chin, S.O.; Chon, S.; Oh, S. et al. Insufficient experience in thyroid fine-needle aspiration leads to misdiagnosis of thyroid cancer. Endocrinol. Metab.; 2014; 29, pp. 293-299. [DOI: https://dx.doi.org/10.3803/EnM.2014.29.3.293]

81. Roncevic, J.; Djoric, I.; Selemetjev, S.; Jankovic, J.; Dencic, T.I.; Bozic, V.; Cvejic, D. MMP-9-1562 C/T single nucleotide polymorphism associates with increased MMP-9 level and activity during papillary thyroid carcinoma progression. Pathology; 2019; 51, pp. 55-61. [DOI: https://dx.doi.org/10.1016/j.pathol.2018.10.008] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30497805]

82. Liu, X.; Su, C.; Xu, J.; Zhou, D.; Yan, H.; Li, W.; Chen, G.; Zhang, N.; Xu, D.; Hu, H. Immunohistochemical analysis of matrix metalloproteinase-9 predicts papillary thyroid carcinoma prognosis. Oncol. Lett.; 2019; 17, pp. 2308-2316. [DOI: https://dx.doi.org/10.3892/ol.2018.9850] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30675296]

83. Marečko, I.; Cvejić, D.; Šelemetjev, S.; Paskaš, S.; Tatić, S.; Paunović, I.; Savin, S. Enhanced activation of matrix metalloproteinase-9 correlates with the degree of papillary thyroid carcinoma infiltration. Croat. Med. J.; 2014; 55, pp. 128-137. [DOI: https://dx.doi.org/10.3325/cmj.2014.55.128]

84. Xu, D.; Su, C.; Guo, L.; Yan, H.; Wang, S.; Yuan, C.; Chen, G.; Pang, L.; Zhang, N. Predictive Significance of Serum MMP-9 in Papillary Thyroid Carcinoma. Open Life Sci.; 2019; 14, pp. 275-287. [DOI: https://dx.doi.org/10.1515/biol-2019-0031]

85. Buergy, D.; Weber, T.; Maurer, G.D.; Mudduluru, G.; Medved, F.; Leupold, J.H.; Brauckhoff, M.; Post, S.; Dralle, H.; Allgayer, H. Urokinase receptor, MMP-1 and MMP-9 are markers to differentiate prognosis, adenoma and carcinoma in thyroid malignancies. Int. J. Cancer; 2009; 125, pp. 894-901. [DOI: https://dx.doi.org/10.1002/ijc.24462]

86. Boltze, C.; Riecke, A.; Ruf, C.G.; Port, M.; Nizze, H.; Kügler, C.; Abend, M. Sporadic and radiation-associated papillary thyroid cancers can be distinguished using routine immunohistochemistry. Oncol. Rep.; 2009; 22, pp. 459-467. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19639189]

87. Selemetjev, S.; Ethoric, I.; Paunovic, I.; Tatic, S.; Cvejic, D. Coexpressed High Levels of VEGF-C and Active MMP-9 Are Associated With Lymphatic Spreading and Local Invasiveness of Papillary Thyroid Carcinoma. Am. J. Clin. Pathol.; 2016; 146, pp. 594-602. [DOI: https://dx.doi.org/10.1093/ajcp/aqw184]

88. Wajner, S.M.; Capp, C.; Brasil, B.A.; Meurer, L.; Maia, A.L. Reduced tissue inhibitor of metalloproteinase-2 expression is associated with advanced medullary thyroid carcinoma. Oncol. Lett.; 2014; 7, pp. 731-737. [DOI: https://dx.doi.org/10.3892/ol.2013.1767]

89. Ivkovic, I.; Limani, Z.; Jakovcevic, A.; Huic, D.; Prgomet, D. Role of Matrix Metalloproteinases and Their Inhibitors in Locally Invasive Papillary Thyroid Cancer. Biomedicines; 2022; 10, 3178. [DOI: https://dx.doi.org/10.3390/biomedicines10123178]

90. Bumber, B.; Marjanovic Kavanagh, M.; Jakovcevic, A.; Sincic, N.; Prstacic, R.; Prgomet, D. Role of matrix metalloproteinases and their inhibitors in the development of cervical metastases in papillary thyroid cancer. Clin. Otolaryngol.; 2020; 45, pp. 55-62. [DOI: https://dx.doi.org/10.1111/coa.13466]

91. Maeta, H.; Ohgi, S.; Terada, T. Protein expression of matrix metalloproteinases 2 and 9 and tissue inhibitors of metalloproteinase 1 and 2 in papillary thyroid carcinomas. Virchows Arch.; 2001; 438, pp. 121-128. [DOI: https://dx.doi.org/10.1007/s004280000286] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11253113]

92. Bayadsi, H.; Barghout, G.; Gustafsson, M.; Sund, M.; Hennings, J. The expression of stromal biomarkers in small papillary thyroid carcinomas. World J. Surg. Oncol.; 2022; 20, 340. [DOI: https://dx.doi.org/10.1186/s12957-022-02805-w]

93. Wang, N.; Jiang, R.; Yang, J.Y.; Tang, C.; Yang, L.; Xu, M.; Jiang, Q.F.; Liu, Z.M. Expression of TGF-beta1, SNAI1 and MMP-9 is associated with lymph node metastasis in papillary thyroid carcinoma. J. Mol. Histol.; 2014; 45, pp. 391-399. [DOI: https://dx.doi.org/10.1007/s10735-013-9557-9]

94. Roncevic, J.; Jankovic Miljus, J.; Isic Dencic, T.; Bozic, V.; Zivaljevic, V.; Selemetjev, S.; Doric, I. Predictive Significance of Two MMP-9 Promoter Polymorphisms and Acetylated c-Jun Transcription Factor for Papillary Thyroid Carcinoma Advancement. Diagnostics; 2022; 12, 1953. [DOI: https://dx.doi.org/10.3390/diagnostics12081953]

95. Zarkesh, M.; Zadeh-Vakili, A.; Akbarzadeh, M.; Fanaei, S.A.; Hedayati, M.; Azizi, F. The role of matrix metalloproteinase-9 as a prognostic biomarker in papillary thyroid cancer. BMC Cancer; 2018; 18, 1199. [DOI: https://dx.doi.org/10.1186/s12885-018-5112-0]

96. Cho Mar, K.; Eimoto, T.; Tateyama, H.; Arai, Y.; Fujiyoshi, Y.; Hamaguchi, M. Expression of matrix metalloproteinases in benign and malignant follicular thyroid lesions. Histopathology; 2006; 48, pp. 286-294. [DOI: https://dx.doi.org/10.1111/j.1365-2559.2005.02325.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16430475]

97. Meng, X.Y.; Zhang, Q.; Li, Q.; Lin, S.; Li, J. Immunohistochemical levels of cyclo-oxygenase-2, matrix metalloproteinase-9 and vascular endothelial growth factor in papillary thyroid carcinoma and their clinicopathological correlations. J. Int. Med. Res.; 2014; 42, pp. 619-627. [DOI: https://dx.doi.org/10.1177/0300060513505485]

98. Zhang, W.J.; Song, B.; Yang, T. MMP-2, MMP-9, TIMP-1, and TIMP-2 in the Peripheral Blood of Patients with Differentiated Thyroid Carcinoma. Cancer Manag. Res.; 2019; 11, pp. 10675-10681. [DOI: https://dx.doi.org/10.2147/CMAR.S233776] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31920377]

99. Pan, Q.; Yuan, T.; Ding, Q. Clinical value of matrix metalloproteinase-2 and -9 in ultrasound-guided radiofrequency ablation treatment for papillary thyroid carcinoma. J. Int. Med. Res.; 2020; 48, 300060520917581. [DOI: https://dx.doi.org/10.1177/0300060520917581]

100. Lin, S.Y.; Wang, Y.Y.; Sheu, W.H. Preoperative plasma concentrations of vascular endothelial growth factor and matrix metalloproteinase 9 are associated with stage progression in papillary thyroid cancer. Clin. Endocrinol.; 2003; 58, pp. 513-518. [DOI: https://dx.doi.org/10.1046/j.1365-2265.2003.01749.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12641636]

101. Li, Y.; He, J.; Wang, F.; Wang, X.; Yang, F.; Zhao, C.; Feng, C.; Li, T. Role of MMP-9 in epithelial-mesenchymal transition of thyroid cancer. World J. Surg. Oncol.; 2020; 18, 181. [DOI: https://dx.doi.org/10.1186/s12957-020-01958-w] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32698816]

102. Liang, H.; Zhong, Y.; Luo, Z.; Huang, Y.; Lin, H.; Luo, M.; Zhan, S.; Xie, K.; Ma, Y.; Li, Q.Q. Assessment of biomarkers for clinical diagnosis of papillary thyroid carcinoma with distant metastasis. Int. J. Biol. Markers; 2010; 25, pp. 38-45. [DOI: https://dx.doi.org/10.1177/172460081002500106] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20306451]

103. Zhang, Y.; Luo, Y.K.; Zhang, M.B.; Li, J.; Li, C.T.; Tang, J.; Li, J.L. Values of ultrasound features and MMP-9 of papillary thyroid carcinoma in predicting cervical lymph node metastases. Sci. Rep.; 2017; 7, 6670. [DOI: https://dx.doi.org/10.1038/s41598-017-07118-7] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28751724]

104. Dragutinovic, V.V.; Tatic, S.B.; Nikolic-Mandic, S.; Savin, S.; Cvejic, D.; Dunderovic, D.; Gajic, M.; Paunovic, I. Matrix metalloproteinase-9 and the Cu/Zn ratio as ancillary diagnostic tools in distinguishing between the classical and follicular variants of papillary thyroid carcinoma. Biol. Trace Elem. Res.; 2012; 149, pp. 29-33. [DOI: https://dx.doi.org/10.1007/s12011-012-9404-y]

105. Zhuang, Z.N.; Xu, Z.J.; Zhou, Q.; Xu, X.Z.; Tian, J.; Liu, Y.F.; Guo, S.; Wang, J.Y.; Xu, K.S. Clinical significance of integrin beta6 as a tumor recurrence factor in follicular thyroid carcinoma. Head Neck; 2015; 37, pp. 1439-1447. [DOI: https://dx.doi.org/10.1002/hed.23780]

106. Dobrescu, R.; Picu, C.; Caragheorgheopol, A.; Manda, D.; Ioachim, D.; Goldstein, A.; Badiu, C. Serum Matrix metalloproteinase-9 (MMP-9) can help identify patients with papillary thyroid cancer at high risk of persistent disease: Value and limitations of a potential marker of neoplasia. Cancer Biomark.; 2020; 29, pp. 337-346. [DOI: https://dx.doi.org/10.3233/CBM-190609]

107. Ouyang, X.; Feng, L.; Yao, L.; Xiao, Y.; Hu, X.; Zhang, G.; Liu, G.; Wang, Z. Testicular orphan receptor 4 (TR4) promotes papillary thyroid cancer invasion via activating circ-FNLA/miR-149-5p/MMP9 signaling. Mol. Ther. Nucleic Acids; 2021; 24, pp. 755-767. [DOI: https://dx.doi.org/10.1016/j.omtn.2021.03.021]

108. Su, Z.; Bao, W.; Yang, G.; Liu, J.; Zhao, B. SOX12 Promotes Thyroid Cancer Cell Proliferation and Invasion by Regulating the Expression of POU2F1 and POU3F1. Yonsei Med. J.; 2022; 63, pp. 591-600. [DOI: https://dx.doi.org/10.3349/ymj.2022.63.6.591]

109. Li, J.; Jiang, L.; Liu, Z.; Li, Y.; Xu, Y.; Liu, H. Oncogenic pseudogene DUXAP10 knockdown suppresses proliferation and invasion and induces apoptosis of papillary thyroid carcinoma cells by inhibition of Akt/mTOR pathway. Clin. Exp. Pharmacol. Physiol.; 2020; 47, pp. 1473-1483. [DOI: https://dx.doi.org/10.1111/1440-1681.13310]

110. Zhang, W.; Sun, W.; Qin, Y.; Wu, C.; He, L.; Zhang, T.; Shao, L.; Zhang, H.; Zhang, P. Knockdown of KDM1A suppresses tumour migration and invasion by epigenetically regulating the TIMP1/MMP9 pathway in papillary thyroid cancer. J. Cell. Mol. Med.; 2019; 23, pp. 4933-4944. [DOI: https://dx.doi.org/10.1111/jcmm.14311]

111. Kummer, N.T.; Nowicki, T.S.; Azzi, J.P.; Reyes, I.; Iacob, C.; Xie, S.; Swati, I.; Darzynkiewicz, Z.; Gotlinger, K.H.; Suslina, N. et al. Arachidonate 5 lipoxygenase expression in papillary thyroid carcinoma promotes invasion via MMP-9 induction. J. Cell. Biochem.; 2012; 113, pp. 1998-2008. [DOI: https://dx.doi.org/10.1002/jcb.24069] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22253131]

112. Luo, D.; Chen, H.; Li, X.; Lu, P.; Long, M.; Peng, X.; Lin, S.; Tan, L.; Zhu, Y.; Ouyang, N. et al. Activation of the ROCK1/MMP-9 pathway is associated with the invasion and poor prognosis in papillary thyroid carcinoma. Int. J. Oncol.; 2017; 51, pp. 1209-1218. [DOI: https://dx.doi.org/10.3892/ijo.2017.4100]

113. Rothhut, B.; Ghoneim, C.; Antonicelli, F.; Soula-Rothhut, M. Epidermal growth factor stimulates matrix metalloproteinase-9 expression and invasion in human follicular thyroid carcinoma cells through Focal adhesion kinase. Biochimie; 2007; 89, pp. 613-624. [DOI: https://dx.doi.org/10.1016/j.biochi.2007.01.015]

114. Kalhori, V.; Törnquist, K. MMP2 and MMP9 participate in S1P-induced invasion of follicular ML-1 thyroid cancer cells. Mol. Cell. Endocrinol.; 2015; 404, pp. 113-122. [DOI: https://dx.doi.org/10.1016/j.mce.2015.01.037]

115. Zhang, X.G.; Lu, X.F.; Jiao, X.M.; Chen, B.; Wu, J.X. PLK1 gene suppresses cell invasion of undifferentiated thyroid carcinoma through the inhibition of CD44v6, MMP-2 and MMP-9. Exp. Ther. Med.; 2012; 4, pp. 1005-1009. [DOI: https://dx.doi.org/10.3892/etm.2012.729] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23226764]

116. Asghar, M.Y.; Kemppainen, K.; Lassila, T.; Törnquist, K. Sphingosine 1-phosphate attenuates MMP2 and MMP9 in human anaplastic thyroid cancer C643 cells: Importance of S1P2. PLoS ONE; 2018; 13, e0196992. [DOI: https://dx.doi.org/10.1371/journal.pone.0196992] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29734379]

117. Jia, W.; Gao, X.J.; Zhang, Z.D.; Yang, Z.X.; Zhang, G. S100A4 silencing suppresses proliferation, angiogenesis and invasion of thyroid cancer cells through downregulation of MMP-9 and VEGF. Eur. Rev. Med. Pharmacol. Sci.; 2013; 17, pp. 1495-1508.

118. Kim, Y.J.; Hwang, H.J.; Kang, J.G.; Kim, C.S.; Ihm, S.H.; Choi, M.G.; Lee, S.J. Enigma Plays Roles in Survival of Thyroid Carcinoma Cells through PI3K/AKT Signaling and Survivin. Anticancer Res.; 2018; 38, pp. 3515-3525. [DOI: https://dx.doi.org/10.21873/anticanres.12623]

119. Ren, L.; Xu, Y.; Liu, C.; Wang, S.; Qin, G. IL-17RB enhances thyroid cancer cell invasion and metastasis via ERK1/2 pathway-mediated MMP-9 expression. Mol. Immunol.; 2017; 90, pp. 126-135. [DOI: https://dx.doi.org/10.1016/j.molimm.2017.06.034]

120. Schneider, D.F.; Chen, H. New developments in the diagnosis and treatment of thyroid cancer. CA Cancer J. Clin.; 2013; 63, pp. 374-394. [DOI: https://dx.doi.org/10.3322/caac.21195] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23797834]

121. Nabhan, F.; Dedhia, P.H.; Ringel, M.D. Thyroid cancer, recent advances in diagnosis and therapy. Int. J. Cancer; 2021; 149, pp. 984-992. [DOI: https://dx.doi.org/10.1002/ijc.33690] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34013533]

122. Zhang, C.Y.; Zhang, L.; Yu, H.X.; Bao, J.D.; Lu, R.R. Curcumin inhibits the metastasis of K1 papillary thyroid cancer cells via modulating E-cadherin and matrix metalloproteinase-9 expression. Biotechnol. Lett.; 2013; 35, pp. 995-1000. [DOI: https://dx.doi.org/10.1007/s10529-013-1173-y] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23474829]

123. Tan, C.; Zhang, L.; Cheng, X.; Lin, X.F.; Lu, R.R.; Bao, J.D.; Yu, H.X. Curcumin inhibits hypoxia-induced migration in K1 papillary thyroid cancer cells. Exp. Biol. Med.; 2015; 240, pp. 925-935. [DOI: https://dx.doi.org/10.1177/1535370214555665] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25349216]

124. Liang, Y.; Kong, D.; Zhang, Y.; Li, S.; Li, Y.; Dong, L.; Zhang, N.; Ma, J. Curcumin inhibits the viability, migration and invasion of papillary thyroid cancer cells by regulating the miR-301a-3p/STAT3 axis. Exp. Ther. Med.; 2021; 22, 875. [DOI: https://dx.doi.org/10.3892/etm.2021.10307] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34194553]

125. Kim, S.H.; Kang, J.G.; Kim, C.S.; Ihm, S.H.; Choi, M.G.; Lee, S.J. Evodiamine Suppresses Survival, Proliferation, Migration and Epithelial-Mesenchymal Transition of Thyroid Carcinoma Cells. Anticancer Res.; 2018; 38, pp. 6339-6352. [DOI: https://dx.doi.org/10.21873/anticanres.12992]

126. Ding, Q.; Li, X.; Sun, Y.; Zhang, X. Schizandrin A inhibits proliferation, migration and invasion of thyroid cancer cell line TPC-1 by down regulation of microRNA-429. Cancer Biomark.; 2019; 24, pp. 497-508. [DOI: https://dx.doi.org/10.3233/CBM-182222]

127. Shi, G.H.; Zhou, L. Emodin suppresses angiogenesis and metastasis in anaplastic thyroid cancer by affecting TRAF6-mediated pathways in vivo and in vitro. Mol. Med. Rep.; 2018; 18, pp. 5191-5197. [DOI: https://dx.doi.org/10.3892/mmr.2018.9510]

128. Wu, W.; Zhou, Q.; Zhao, W.; Gong, Y.; Su, A.; Liu, F.; Liu, Y.; Li, Z.; Zhu, J. Ginsenoside Rg3 Inhibition of Thyroid Cancer Metastasis Is Associated with Alternation of Actin Skeleton. J. Med. Food; 2018; 21, pp. 849-857. [DOI: https://dx.doi.org/10.1089/jmf.2017.4144]

129. Zhu, J.; Li, X.; Zhang, S.; Liu, J.; Yao, X.; Zhao, Q.; Kou, B.; Han, P.; Wang, X.; Bai, Y. et al. Taraxasterol inhibits TGF-beta1-induced epithelial-to-mesenchymal transition in papillary thyroid cancer cells through regulating the Wnt/beta-catenin signaling. Hum. Exp. Toxicol.; 2021; 40, (Suppl. S12), pp. S87-S95. [DOI: https://dx.doi.org/10.1177/09603271211023792]

130. De Amicis, F.; Perri, A.; Vizza, D.; Russo, A.; Panno, M.L.; Bonofiglio, D.; Giordano, C.; Mauro, L.; Aquila, S.; Tramontano, D. et al. Epigallocatechin gallate inhibits growth and epithelial-to-mesenchymal transition in human thyroid carcinoma cell lines. J. Cell. Physiol.; 2013; 228, pp. 2054-2062. [DOI: https://dx.doi.org/10.1002/jcp.24372]

131. Rajoria, S.; Suriano, R.; George, A.; Shanmugam, A.; Schantz, S.P.; Geliebter, J.; Tiwari, R.K. Estrogen induced metastatic modulators MMP-2 and MMP-9 are targets of 3,3′-diindolylmethane in thyroid cancer. PLoS ONE; 2011; 6, e15879. [DOI: https://dx.doi.org/10.1371/journal.pone.0015879] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21267453]

132. Shang, H.; Wang, S.; Yao, J.; Guo, C.; Dong, J.; Liao, L. Salidroside inhibits migration and invasion of poorly differentiated thyroid cancer cells. Thorac. Cancer; 2019; 10, pp. 1469-1478. [DOI: https://dx.doi.org/10.1111/1759-7714.13096] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31120636]

133. Goncalves, C.F.L.; Hecht, F.; Cazarin, J.; Fortunato, R.S.; Vaisman, M.; Carvalho, D.P.; Ferreira, A.C.F. The flavonoid quercetin reduces cell migration and increases NIS and E-cadherin mRNA in the human thyroid cancer cell line BCPAP. Mol. Cell. Endocrinol.; 2021; 529, 111266. [DOI: https://dx.doi.org/10.1016/j.mce.2021.111266] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33831503]

134. Oh, S.J.; Jung, S.P.; Han, J.; Kim, S.; Kim, J.S.; Nam, S.J.; Lee, J.E.; Kim, J.H. Silibinin inhibits TPA-induced cell migration and MMP-9 expression in thyroid and breast cancer cells. Oncol. Rep.; 2013; 29, pp. 1343-1348. [DOI: https://dx.doi.org/10.3892/or.2013.2252]

135. Li, Y.; Zeng, Q.G.; Qiu, J.L.; Pang, T.; Wang, H.; Zhang, X.X. Sevoflurane inhibits the progression of PTC by downregulating miR-155. Eur. Rev. Med. Pharmacol. Sci.; 2019; 23, pp. 6579-6587. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31378899]

136. Kalhori, V.; Magnusson, M.; Asghar, M.Y.; Pulli, I.; Tornquist, K. FTY720 (Fingolimod) attenuates basal and sphingosine-1-phosphate-evoked thyroid cancer cell invasion. Endocr. Relat. Cancer; 2016; 23, pp. 457-468. [DOI: https://dx.doi.org/10.1530/ERC-16-0050]

137. Haghpanah, V.; Malehmir, M.; Larijani, B.; Ahmadian, S.; Alimoghaddam, K.; Heshmat, R.; Ghavamzadeh, A.; Adabi, K.; Ghaffari, S.H. The Beneficial Effects of Valproic Acid in Thyroid Cancer Are Mediated through Promoting Redifferentiation and Reducing Stemness Level: An In Vitro Study. J. Thyroid Res.; 2014; 2014, 218763. [DOI: https://dx.doi.org/10.1155/2014/218763]

138. Zhang, D.; Wan, L.; Zhang, J.; Liu, C.; Sun, H. Effect of BMAP-28 on human thyroid cancer TT cells is mediated by inducing apoptosis. Oncol. Lett.; 2015; 10, pp. 2620-2626. [DOI: https://dx.doi.org/10.3892/ol.2015.3612]

139. Chiang, K.C.; Kuo, S.F.; Chen, C.H.; Ng, S.; Lin, S.F.; Yeh, C.N.; Chen, L.W.; Takano, M.; Chen, T.C.; Juang, H.H. et al. MART-10, the vitamin D analog, is a potent drug to inhibit anaplastic thyroid cancer cell metastatic potential. Cancer Lett.; 2015; 369, pp. 76-85. [DOI: https://dx.doi.org/10.1016/j.canlet.2015.07.024]

140. Kim, S.H.; Kang, J.G.; Kim, C.S.; Ihm, S.H.; Choi, M.G.; Yoo, H.J.; Lee, S.J. Synergistic cytotoxicity of the dipeptidyl peptidase-IV inhibitor gemigliptin with metformin in thyroid carcinoma cells. Endocrine; 2018; 59, pp. 383-394. [DOI: https://dx.doi.org/10.1007/s12020-017-1503-2]

141. Lee, S.Y. Anti-Metastatic and Anti-Inflammatory Effects of Matrix Metalloproteinase Inhibition by Ginsenosides. Biomedicines; 2021; 9, 198. [DOI: https://dx.doi.org/10.3390/biomedicines9020198] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33671187]

142. Li, L.; Wang, Y.; Qi, B.; Yuan, D.; Dong, S.; Guo, D.; Zhang, C.; Yu, M. Suppression of PMA-induced tumor cell invasion and migration by ginsenoside Rg1 via the inhibition of NF-kappaB-dependent MMP-9 expression. Oncol. Rep.; 2014; 32, pp. 1779-1786. [DOI: https://dx.doi.org/10.3892/or.2014.3422] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25174454]

143. Chang, J.W.; Kang, S.U.; Shin, Y.S.; Kim, K.I.; Seo, S.J.; Yang, S.S.; Lee, J.S.; Moon, E.; Lee, K.; Kim, C.H. Non-thermal atmospheric pressure plasma inhibits thyroid papillary cancer cell invasion via cytoskeletal modulation, altered MMP-2/-9/uPA activity. PLoS ONE; 2014; 9, e92198. [DOI: https://dx.doi.org/10.1371/journal.pone.0092198] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24667444]

144. Jiang, J.; Wang, K.; Chen, Y.; Chen, H.; Nice, E.C.; Huang, C. Redox regulation in tumor cell epithelial-mesenchymal transition: Molecular basis and therapeutic strategy. Signal Transduct. Target. Ther.; 2017; 2, 17036. [DOI: https://dx.doi.org/10.1038/sigtrans.2017.36] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29263924]

145. Vosgha, H.; Ariana, A.; Smith, R.A.; Lam, A.K. miR-205 targets angiogenesis and EMT concurrently in anaplastic thyroid carcinoma. Endocr. Relat. Cancer; 2018; 25, pp. 323-337. [DOI: https://dx.doi.org/10.1530/ERC-17-0497]

146. Liu, F.; Lou, K.; Zhao, X.; Zhang, J.; Chen, W.; Qian, Y.; Zhao, Y.; Zhu, Y.; Zhang, Y. miR-214 regulates papillary thyroid carcinoma cell proliferation and metastasis by targeting PSMD10. Int. J. Mol. Med.; 2018; 42, pp. 3027-3036. [DOI: https://dx.doi.org/10.3892/ijmm.2018.3902]

147. You, A.; Fu, L.; Li, Y.; Li, X.; You, B. MicroRNA-203 restrains epithelial-mesenchymal transition, invasion and migration of papillary thyroid cancer by downregulating AKT3. Cell Cycle; 2020; 19, pp. 1105-1121. [DOI: https://dx.doi.org/10.1080/15384101.2020.1746490]

148. Zhu, Y.; Zhao, J.; Tan, L.; Lin, S.; Long, M.; Peng, X. LncRNA-HCG18 regulates the viability, apoptosis, migration, invasion and epithelial-mesenchymal transition of papillary thyroid cancer cells via regulating the miR-106a-5p/PPP2R2A axis. Pathol. Res. Pract.; 2021; 221, 153395. [DOI: https://dx.doi.org/10.1016/j.prp.2021.153395] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33798913]

149. Li, N.; Cui, M.; Yu, P.; Li, Q. Correlations of lncRNAs with cervical lymph node metastasis and prognosis of papillary thyroid carcinoma. OncoTargets Ther.; 2019; 12, pp. 1269-1278. [DOI: https://dx.doi.org/10.2147/OTT.S191700]

150. Min, X.; Liu, K.; Zhu, H.; Zhang, J. Long Noncoding RNA LINC003121 Inhibits Proliferation and Invasion of Thyroid Cancer Cells by Suppression of the Phosphatidylinositol-3-Kinase (PI3K)/Akt Signaling Pathway. Med. Sci. Monit.; 2018; 24, pp. 4592-4601. [DOI: https://dx.doi.org/10.12659/MSM.908652]

151. Cui, W.; Xue, J. Circular RNA DOCK1 downregulates microRNA-124 to induce the growth of human thyroid cancer cell lines. Biofactors; 2020; 46, pp. 591-599. [DOI: https://dx.doi.org/10.1002/biof.1662] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32584497]