Inflammation-induced cellular changes: Genetic mutations, oncogene impact, and novel glycoprotein biomarkers

Abstract

Persistent inflammation can trigger the development of colorectal cancer, especially in patients with inflammatory bowel disease (IBD). The precise molecular mechanisms underlying this process are not fully understood. This study investigated the molecular modifications that occur in the cellular microenvironment during inflammation-induced and colitis-associated cancers. Studies showed that genetic mutations and post-translational modifications of oncogene proteins can alter the biological functions of macrophage inflammatory proteins, complicating the intricate interactions between inflammation and cancer. The researchers also observed abnormal glycosylation patterns in cases of inflammation and colitis-associated cancers. This observation suggests that glycoproteins present in bodily fluids could potentially serve as valuable disease markers. Additionally, the researchers investigated general signaling alterations that manifest in cases of colitis-associated cancer. They proposed a provisional molecular model that suggests the involvement of endoplasmic reticulum (ER) stress during the transition from inflammation to cancer. This potential pathway is mediated through the FKBP/c-Myc/p53 signaling axis. In the context of protein glycosylation, we summarize the potential molecular mechanisms of IBDinduced carcinogenesis. This knowledge could potentially lead to the development of novel targets for the clinical treatment of colorectal cancer.

Headnote

ABSTRACT

Persistent inflammation can trigger the development of colorectal cancer, especially in patients with inflammatory bowel disease (IBD). The precise molecular mechanisms underlying this process are not fully understood. This study investigated the molecular modifications that occur in the cellular microenvironment during inflammation-induced and colitis-associated cancers. Studies showed that genetic mutations and post-translational modifications of oncogene proteins can alter the biological functions of macrophage inflammatory proteins, complicating the intricate interactions between inflammation and cancer. The researchers also observed abnormal glycosylation patterns in cases of inflammation and colitis-associated cancers. This observation suggests that glycoproteins present in bodily fluids could potentially serve as valuable disease markers. Additionally, the researchers investigated general signaling alterations that manifest in cases of colitis-associated cancer. They proposed a provisional molecular model that suggests the involvement of endoplasmic reticulum (ER) stress during the transition from inflammation to cancer. This potential pathway is mediated through the FKBP/c-Myc/p53 signaling axis. In the context of protein glycosylation, we summarize the potential molecular mechanisms of IBDinduced carcinogenesis. This knowledge could potentially lead to the development of novel targets for the clinical treatment of colorectal cancer.

Keywords:

Inflammatory bowel disease

Colitis

Colitis-associated cancer

Cancer

Glycosylation

1. Chronic inflammatory microenvironment in cancer

Inflammation stands as a cancer hallmark, with some tumors originating from sites of persistent inflammation even after inflammation subsides.1 Its roles encompass disease spread,2 tumor resistance to treatment,3 and inhibition of innate anticancer immunity.4 Chronic inflammation notably elevates the risk of cervical and colorectal cancer. Inflammatory bowel disease (IBD) patients face notably heightened colorectal cancer risk (CRC) due to chronic intestinal inflammation's pro-neoplastic impact.5,6 Ulcerative colitis (UC) patients, for instance, exhibit a six-fold higher CRC risk than the general population, along with a heightened occurrence of multiple synchronous CRCs.7 Colon inflammation prompts constant gut lining cell turnover, leading to tissue irregularities.8

Inflammation arises as a response to tissue injury, initiating a chemical signaling cascade to activate an immune response, crucial for tissue healing. These signals trigger leukocyte chemotaxis from circulation to the injury site, yielding cytokines that drive inflammation.9 Under inflammatory conditions or mutagenesis, stem or progenitor cells may undergo transformation, with chronic inflammation potentially initiating and promoting cancer cell development (Fig. 1). Commonly elevated in inflammatory states, cytokines like interleukin-6 (IL-6) and IL-1 can further induce upregulation of chemokines such as CXCL5 and CXCL2. 10,11 Conversely, acute inflammation fosters cancer cell demise via antitumor immune responses, thwarting cancer cell formation or transformation.12

Mounting evidence underscores the capacity of chronic inflammation to reshape the tumor microenvironment (TME), a pivotal component in most tumors.13 The TME encompasses blood vessels, immune cells, fibroblasts, signaling molecules, and extracellular matrix encircling a tumor. This milieu plays a determining role in tumor differentiation, epigenetics, dissemination, and evasion of the immune system. Biochemical cues within the TME hold sway over cellular behavior, metastatic potential, and attributes of cancer stem cells. Immune cells within the TME can be influenced to attenuate their antitumor functions, conceivably promoting tumor expansion.14 Chronic inflammation fosters angiogenesis, fostering new blood vessels that escalate tissue nourishment and facilitate tumor progression.15 Inflammatory cells and factors collaborate to assist tumor cells in evading immune surveillance.13 Research demonstrates reciprocal interplay between fibroblasts and inflammatory cells, altering fibroblasts to spur extracellular matrix production.16 Cancer-associated fibroblasts (CAFs) can regulate cancer cell migration and invasion by releasing growth factors like FGFs and cytokines, which remodel the TME, thus modulating growth factor signaling and extracellular architecture.17 Such changes might disturb protein glycosylation as inflammatory cytokines influence the expression of glycoenzymes engaged in tumor-associated glycan synthesis.18

Within the inflammatory TME, alterations in tumor cell glycosylation are initiated, with changes in glycans definitively fueling the establishment and perpetuation of inflammation that supports tumor growth.19,20 Investigations have highlighted the role of glycans in shaping the TME and propelling T cell-mediated immune responses against tumors.21 In this context, T cells within the TME display intricate N-glycan structures that elevate the activation threshold of the T cell receptor (TCR), leading to increased surface expression of inhibitory molecules like CTLA-4 and PD-1.22, 23 Notably, key glycoenzymes like GnT-IV, GnT-V, and ST6Gal-I are frequently upregulated in colon and breast cancers. This elevation results in tumor cell surfaces adorned with highly branched α2,3- and/or α2, 6-linked sialic acids, subsequently reducing cell-cell adhesion.24

2. IBD-induced gene and protein mutation

Variation of the tumor microenvironment (TME) can trigger somatic oncogene mutations,25 while inflammation is responsible for DNA damage, gene mutations, and eventual tumorigenesis.26 The inflammatory process accompanies an elevation in reactive oxygen or nitrogen species (ROS or RON) levels, inflicting DNA damage (Fig. 2). This imbalance, where increased RONs surpass their neutralization capacity, induces oxidative stress to exacerbate inflammation in the gastrointestinal tract (GIT) and incite IBD.27 RONs have the capacity to oxidize DNA bases and compromise DNA strands as free radicals assault their sugar-phosphate backbone, a hallmark of cancer.28 Conversely, DNA damage can also incite the production of ROS through the H2AX-Nox1/Rac1 pathway, marked by elevated H2AX histone modification.29 ROS, functioning as a mitogenic signaling molecule, fuels aberrant tumor cell proliferation driven by oncogenic Ras.30 The DNA damage response (DDR) at the cellular level triggers cell death, senescence, or apoptosis due to telomere shortening, where senescence's gene expression pattern mirrors that of the inflammatory response. Intriguingly, senescent cells are a wellspring of chronic inflammation, as fibroblast and epithelial cellular senescence is accompanied by a notable surge in secreted factors that partake in intercellular signaling.31 Ultimately, RONS induced by colitis contribute to oncogenic mutations in IBD, including UC and CD (Fig. 2).

Colitis-associated oncogene mutation. IBD can trigger oncogene mutations that elevate the susceptibility to colon adenocarcinoma. A variety of cellular processes governing intestinal homeostasis employ distinct networks to facilitate immune tolerance, inflammation, or epithelial restoration. Sequential occurrences of somatic genetic mutations due to chronic inflammation have been identified as the driving force behind colon carcinogenesis in IBD.32 Notably, certain IBD-associated genes influence epithelial structure and function, including safeguarding the mucosa against gut microbiota. For instance, DUSP16 (or MKP-7) and KSR1 play pivotal roles in intestinal homeostasis, orchestrating MAPK activity in intestinal epithelial cells to induce PIGR expression.33 Additionally, research has noted significant KSR1 overexpression in human colon tumor cell lines. This heightened KSR1, alongside EPHB4, synergistically fosters tumor cell viability by promoting downstream c-Myc and the transcriptional co-activator PGC1-β. 34

Genome-wide association studies (GWAS) have pinpointed over 70 and 47 risk loci in CD and UC, respectively, with 28 demonstrating shared associations.35 Diverse genes have demonstrated links to UC in specific populations, including TNF-α, STAT3, and JAK2. 36 JAK2 and TYK2 are pivotal in the signaling of interleukins like IL-6, IL-22, or IL-23. JAK2 governs the STAT pathway's transcriptional factor, and these interleukins can activate inflammasomes via these pathways to expedite tumor cell proliferation.37 Mutations like JAK1-V658F and JAK3-V715I, recurring in common human cancers, potentially contribute to cancer progression.38 TNF-α, a pro-inflammatory cytokine discharged by macrophages during acute inflammation, triggers NF-kB activation, subsequently prompting ROS generation through NADPH oxidase activation.39

Genetic variations can impact the gut microbiota composition and exert detrimental effects on intestinal cell functions. Notably, ATG16L1, IL23R, IRGM, and NOD2 genes demonstrate an apparent propensity to increase the risk of CD (Fig. 2).40 Among these, NOD2, located on chromosome 16q12, activates NF-kB in response to bacterial lipopolysaccharides (LPS), a constituent of Gram-negative bacterial outer membranes encompassing lipid, core oligosaccharide, and distal polysaccharide domains.41 This substantially elevates CD susceptibility, a unique association not shared with UC. ATG16L1 variants exacerbate caspase 3 degradation in CD, inducing alterations in autophagy and innate immune responses.42 Notably, loss of epithelial-specific ATG16L1 and autophagy intensifies acute injury and inflammation, precipitating diminished survival.43 The immunity-related GTPase (IRGM), an autoimmune-associated gene,

governs anti-inflammatory processes while bolsters tumor cell survival through autophagy.44 IRGM engages GTP and regulates selective autophagy encompassing xenophagy and mitophagy. Elevated IRGM expression may coincide with augmented cell colony formation, proliferation, and Akt activation through p62/TRAF6/NF-kB signaling.45 Drawing on population studies examining NOD2, IL23R, and ATG16L1 polymorphisms, mutations within these genes have demonstrated associations with CD.46

Human inflammation-induced protein mutation. In the context of trauma, stress, or infection, inflammatory proteins present in the bloodstream contribute to reinstating homeostasis and curtailing microbial growth, operating independently from antibodies.47 Table S1 compiles a total of 57 human inflammatory proteins, delineating their functions in inflammation and tumorigenesis. Through cross-referencing TCGA and GEPIA databases, the expression of these proteins was juxtaposed across IBD, CRC, and normal tissues. Notably, interleukins secreted by blood cells play diverse roles in inflammation progression, immune activation, and the generation of pro-inflammatory cytokines and chemokines. For instance, IL11 induced by colitis triggers STAT3 signaling in cancer-associated fibroblasts, thereby fostering colon carcinogenesis and tumor advancement.48 Conversely, escalated mucosal IL12 levels prominently correspond to UC exacerbation, as IL12 directs T cells toward type 1 T helper (Th1) polarization, which then activates NK cells, innate lymphoid cells type 1 (ILC1), and type 1 cytotoxic T cells. This activation cascades into the production of INF-γ, TNF-α, and perforin.49,50 The IL21 cytokine tilts the balance towards Th1 differentiation, perpetuating chronic inflammation while diminishing tumor immunosurveillance and fostering a tumor-favoring microenvironment in the colon.51 S100 calcium-binding proteins, frequently upregulated in IBD, substantiate cell proliferation, differentiation, survival, migration, and inflammation. Certain S100 calcium-binding proteins possess the ability to be secreted and regulate cellular functions by engaging surface receptors, including platelet glycoprotein 4 (CD36), fibroblast growth factor receptor 1 (FGFR1), advanced glycation end-products, or toll-like receptor 4 (TLR4).52 Remarkably, these proteins boast significant glycosylation, alterations of which could profoundly reshape their interactions with S100 calcium-binding proteins.53,54

In CRC, the regulatory dynamics of inflammatory proteins diverge from those in normal tissues. Fold-changes (FC) were derived from gene expression data in CRC and normal tissues (Table S1). Chemokine ligands display elevated expression levels in CRC, alongside increased levels of IL1B, IL26, IL26G, and IL7. Notably, NOS2, S100P, and S100A14 exhibit substantial upregulation in CRC. The construction of protein-protein networks was undertaken using STRING, based on TCGA data and considering gene FC above 1.5 or below 0.67.55 ANXA1 demonstrates interaction with a multitude of S100 proteins, whereas LGALS1 interfaces with S00A11. Concurrently, heightened expression of ICAM-1 was positively correlated with advanced CRC. ICAM-1 functions as an adapter protein for p-SRC, exerting regulatory control over CRC malignancy.56,57 Phosphorylation of ICAM-1 by tyrosine-protein kinase c-MET and its ensuing phosphorylation serve as cofactors in SRC signaling activity. This culminates in STAT3 upregulation, inducing EMT (Fig. 3A).56 Conversely, TLR4 exhibits robust expression in CRC and showcases direct correlation with the survival of CRC patients. Augmented TLR4 activity fuels tumor growth, metastasis, and immune surveillance.58 The TLR4 and myeloid differentiation factor 2 (MD-2) complex interacts with Gram-negative bacterial LPS, evoking an innate immune response. Notably, this complex can be activated by chemically synthesized neoseptins, eliciting comparable effects.59 The TLR4/MD-2 complex amplifies the transcriptional factor NF-kB and downstream genes, orchestrating the mediation of inflammatory cytokines and adhesion molecules (Fig. 3A).60 Phosphorylation of TLRs and ADP (adenosine diphosphate) occasions an upswing in inflammasome expression, culminating in the maturation of IL-1β from its proinflammatory precursor. Secreted IL-1β in turn governs tumor-associated macrophages (TAM), neutrophils (Neu), and myeloid-derived suppressor cells (MDSC) (as illustrated in Fig. 3C). Of particular relevance, secreted IL-1β instigates the activation of the IL-1 receptor, a pivotal factor in tumor development.61

Numerous oncogenes and tumor suppressor genes (TSGs) play pivotal roles in driving tumorigenesis and metastasis. Fig. 3B shows tissue-specific oncogenes and TSGs within the human brain, lung, arm, liver, and gastrointestinal tract, with the font size indicative of the relative regulation potency of the oncogenic pathway. Signaling pathways exhibit diversity across distinct organs such as the brain, lung, liver, or stomach. Genetic alterations frequently entail the activation of proto-oncogenes (e.g., KRAS, BAX) and the inactivation of TSGs (e.g., APC, p53).62,63 The p53 signaling pathway, a pivotal tumor suppressor route, exerts extensive regulatory influence over nearly all organs, prominently the lung, liver, breast, stomach, and colon. The transcription factor p53 orchestrates diverse cellular responses to counteract colon tumor development. Activation of p53 can be initiated by NO or ROS, underscoring its central role.64 Interestingly, c-MYC activation can instigate tumor cell apoptosis via the p53 signaling route, concurrently inducing DNA damage while curtailing p53 functionality.65

Genes involved in colitis-associated cancer (CIC). Inflammatory stimuli can expedite tumorigenesis and its progression by elevating the mutation rate of oncogene regulators. To comprehensively investigate the mechanistic linkage between inflammation and cancer, we conducted a comprehensive analysis of pivotal genes intricately involved in colitis-associated tumorigenesis. Existing studies have elucidated how inflammation can engender heightened miR155 levels, culminating in the attenuation of WEE1 (Wee1like protein kinase), an essential contributor to DNA repair. This elevation leads to an augmented frequency of spontaneous genetic mutations, ultimately fostering cancer development.66 WEE1 serves as a mitotic checkpoint kinase, orchestrating cell cycle regulation and thereby emerging as an attractive target for RAS-mutated cancer therapy.67 In tandem with its overexpression, miR-155 stimulation amplifies the incidence of HPRT (hypoxanthine phosphoribosyltransferase) mutations while concomitantly downregulating WEE1, constituting a mechanism underpinning inflammation-driven tumorigenesis.66 Chronic inflammation, typified by IBD, incites DNA damage and detriment to colonic epithelial cells, ultimately seeding the terrain for colonic tumorigenesis.68 Furthermore, inflammation might serve as both a driver and vulnerability within KRAS-mutant tumors arising from the epithelial lining of the pancreas, colon, and lung.69 Del Poggetto and associates unveiled a dynamic phenomenon in pancreatic cells, wherein recurrent inflammation initially exerts an adaptive response forestalling tissue harm, yet subsequently fosters tumor genesis when coupled with a KRAS G12D mutation.70

The epithelium of UC prominently exhibits somatic mutations in inflammatory genes, among them NFKBIZ, ZC3H12A, and PIGR. 71 Within this context, IFIH1 mutations impair gut antiviral proteins, rendering patients susceptible to a rare manifestation of IBD.72 A contemporary approach utilizes iScores to establish a correlation between inflammation levels and patient survival, revealing that those with the lowest iScores generally experience prolonged survival.73 In the realm of acute myeloid leukemia (AML), utilizing bone marrow samples from 20 adults and 22 children, an intriguing observation emerged wherein more than a dozen gene mutations linked with elevated iScores were prevalent in cases of severe AML. The efficacy of certain immune T cells, responsible for direct cancer cell targeting, was suppressed in pediatric leukemia cases characterized by high inflammation, whereas this suppression was not witnessed in adult counterparts manifesting heightened inflammation.74 Evidently, inflammation can serve as a driver for mutagenesis, and concurrently, genetic mutations can elicit inflammatory responses.

3. Aberrant glycosylation in inflammation-induced colorectal cancer

Glycosylation exerts regulatory influence over immune cell functionality by orchestrating the recruitment of leukocytes to inflammatory sites, eliciting either pro-inflammatory or anti-inflammatory effects. Consequently, aberrant glycosylation processes may underpin the onset of inflammatory disorders. In the context of CRC, truncated O-glycans, notably aberrant O-glycosylation, have been robustly associated. Of significance, CD44 antigen's glycosylation profile governs its behavior; elevated sialofucosylation enables selectin binding, thereby propelling CRC metastasis.75 Across the digestive system's surface, viscoelastic mucous gel layers or transmembrane mucins, substantially O-glycosylated, are prevalent. Tn, T, sialyl Tn or sialyl T antigens are abundant in cancerous tissues. Fig. 4 illustrates the O-glycosylation distribution within the human digestive tract. The small intestine predominantly features mucin-type core 3 O-glycan (GlcNAc(β1-3)GalNAc), while the large intestine prominently expresses core 3 and core 4 (GlcNAc(β1-3) [GlcNAc(β1-6)]-GalNAc). As one progresses from the duodenum to the large intestine, sialylation and GalNAcylation exhibit a gradual ascent, contrasting the diminishing fucosylation trend.76 In contrast to the colon, the stomach predominantly encompasses mucin-type core 1 and core 2 O-glycans - Gal(β1-3)GalNAc and Gal(β1-3)[GlcNAc(β1-6)]-GalNAc, respectively. Differential O-glycomics across intestinal segments unveil the prevalence of specific glycan structures. For instance, the small intestine stands out for heightened fucosylation, the distal colon features sulpho-LeX core 2 O-glycans, and the ileum or cecum harbors blood group H/A epitopes.77 Collectively, these findings underscore the potential utility of tissue-specific O-glycosylation profiles in diagnosing diverse tissue-related diseases.78–80

Aberrant glycosylation in the pathogenesis of IBD and CIC. Aberrant glycosylation processes wield substantial influence over the functionality of numerous glycoproteins within the gastrointestinal milieu, contributing to the pathophysiology of IBD.81 A considerable portion of this effect arises from the intricate glycan structures, including N- or O-linked glycans, present on intestinal epithelial cells.82 These glycans play a pivotal role in fortifying barrier function and safeguarding against toxins and pathogens, thereby nurturing mucosal homeostasis.76 As documented by the HUGO Gene Nomenclature Committee, human tissues harbor a collection of 21 MUC genes (Table S2), wherein MUC13, MUC2, MUC12, and MUC1 stand as the most prevalent (Table 1). MUC2 protein takes center stage as an abundant glycoprotein within colonic goblet cells,83 whereas MUC5B dominates at the crypt base, exhibiting relatively lower expression within goblet or absorptive cells.84 A substantial 80 % of MUC2's molecular weight is composed of oligosaccharide side chains, orchestrating water binding to craft a protective mucus gel, which effectively shields the MUC2 backbone against host digestion and bacterial proteases. It's noteworthy that MUC2-deficient mice display heightened susceptibility to colitis induced by dextran sulphate sodium (DSS).85 The O-glycosylation of MUC2 is amenable to regulatory modulation through differential bacterial glycoenzyme expression.86 A striking observation is the prominent elevation of T cell core fucosylation in IBD patients due to augmented FUT8 within the T-cell receptor. This phenomenon impedes core fucosylation synthesis, thereby presenting a potential avenue for therapeutic intervention.87 Notably, despite the central significance of MUC proteins, comprehensive characterization remains a challenge, primarily attributed to their extended tandem-repeats (TR) structures, extensively O-glycosylated to counter protease degradation.

Mucin glycosylation frequently exhibits correlation with the processes of tumorigenesis and metastasis. The variable number of tandem repeats (VNTR) rich in Ser, Thr, or Pro residues within mucins undergo substantial O-glycosylation. Transmembrane mucins anchored to the cell surface govern antigenicity, enabling interactions and binding with mammalian lectins.88 The sialyl O-glycans of MUC1 have demonstrated the ability to augment the growth rate of breast cancer cells, with sialic acids also implicated in the metastatic cascade.89 Lectin affinity analyses have indicated notably elevated T antigen expression on MUC1 in CRC patients, while CEACAM5 carries heightened levels of LeX and LeY in CRC tissues.90 Deletion of MUC5B has been shown to induce alterations in tumorigenic properties via the Wnt/β-catenin pathway in gastrointestinal cancer cells.91 Conversely, exogenous expression of MUC13 has exhibited the capacity to amplify tumorigenic traits, including tumor cell growth, colony formation, and cell migration.92

Furthermore, a multitude of glycoproteins experience modification in CRC patients, with observed upregulation of N-glycosylation in serum (PLOD2, LAMP3, DPEP1, CD82).93

CIC-associated biomarkers present in human biofluids. The inflammatory response is acknowledged to induce significant alterations in plasma protein composition, including reductions in albumin and transferrin, as well as increased levels of haptoglobin and immunoglobulin.94 Plasma contains acute-phase proteins (APPs) that undergo concentration changes in response to inflammation. Hence, plasma proteins such as serum amyloid A (SAA1), C-reactive protein (CRP), α1-antichymotrypsin (SERPINA3), and α1-acid glycoprotein (AGP1) have been investigated for their potential in monitoring inflammatory bowel disease (IBD).95,96 Given that abnormal glycosylation can characterize tumor malignancy, there is potential to identify CIC glycoprotein biomarkers. CA125 (MUC16) has been documented to be elevated in individuals with IBD, CRC, and ovarian cancer.97 However, it is not a very specific biomarker because its level can be elevated by endometriosis or pregnancy. This suggests that solely evaluating protein levels may not distinguish between IBD and CRC, but their distinct glycosylation patterns might offer differentiation. Leucine-rich α-2 glycoprotein (LRG1) levels show promise in differentiating mucosal healing from endoscopic activity in UC and CD.98 However, the usefulness of serum LRG as a specific marker is limited because its levels can also be elevated in autoimmune diseases, CRC, and gastric cancer. Interestingly, when LRG1 was isolated from pancreatic or CRC serum, discernible glycosylation variations were observed in terms of mannose, fucose, and sialic acid content. This indicates that modified glycosylation could impact its role in cancer.99 Given the pronounced variability of glycosylation across different human body fluids or tissues, it becomes imperative to employ consistent biological samples for the discovery of potential biomarkers.100,101 A judicious approach involves segregating human body fluids from tissues for a targeted examination of glycosylation in individual tissues or fluids, often facilitated by filter-assisted vacuum methods.102 Additional critical glycoprotein biomarkers are enumerated in Table 2.

4. General signaling alteration in CIC

The prevailing consensus suggests that CICs undergo a progression marked by inflammation, dysplasia, adenoma, and eventually adenocarcinoma. In this evolutionary trajectory, inflammatory factors assume a pivotal role, manifesting distinctive attributes of inflammation-cancer transformation. Compelling substantiation arises from the clinical utilization of non-steroidal anti-inflammatory drugs (NSAID), which substantially curtail cancer risk by up to 60 % in patients afflicted with IBD.103 Inflammatory factors wield the capability to propel tumorigenesis through epigenetic mechanisms. For instance, interleukin-6 (IL-6) can activate DNA methyltransferases DNMT1/2 in intestinal epithelial cells, thereby inducing methylation modifications in tumor suppressor gene APC. This leads to cell proliferation and the instigation of malignant transformation.104 Nonetheless, the precise mechanism bridging the transition from inflammation to cancer remains enigmatic. Multiple investigations have unveiled endoplasmic reticulum stress (ERS) as a shared molecular mechanism in both IBD and CRC.105,106 ERS can disrupt the production and secretion of mature MUC2 within goblet cells, thereby impairing barrier function in vitro. 107 MUC2 plays a dual role, not only participating in the onset and advancement of IBD through pathways such as IRE1α/JNK, ATF6-DAPK1, but also implicating itself in the genesis of malignant tumors, notably colorectal cancer, through pathways like Wnt/β-catenin or PERK-eIF2α. 108–110

Certain proteins associated with ERS might contribute to the genesis of IBD-related carcinogenesis. Mechanistic investigations into ERS-associated IBD progression have identified FKBP11 as an abundantly expressed ERS-associated protein in the colon tissue of individuals with IBD. FKBP11 exhibits inhibitory effects on IFN-γ/TNF-α-induced apoptosis in intestinal epithelial cells by impeding the JNK/caspase signaling pathway.111 Part of the FK506-binding protein family, FKBP11 possesses peptidyl-prolyl-cis-trans isomerase (PPIase) activity, pivotal in inflammatory and immune responses, protein folding, transport, and neural growth.112 The relevance of FKBP11 extends to various inflammatory diseases and tumors, demonstrated by its heightened expression in systemic lupus erythematosus patients' B cells, wherein it modulates the expression and differentiation of essential transcription factors like PAX5, BACH2, and AICDA in B cells or plasma cells.113 In the context of autoimmune tolerance, FKBP11 underpins cell differentiation and autoantibody generation through B cell responses to foreign antigens

Elevated free fatty acid levels induce FKBP11 expression in pancreatic β-cells, maintaining cellular homeostasis via the unfolded protein response (UPR)-induced transcription factor C/EBP homologous protein (CHOP). However, persistent activation of the ERS pathway leads to insulin resistance in type 2 diabetes.111,114 FKBP11 has been posited as an early marker for liver cancer, given its markedly higher expression in patients with liver cancer coexisting with viral hepatitis. The expression of FKBP11 exhibits a progressive increase in liver tissues from patients with hepatitis, benign liver lesions, histologically normal tissue adjacent to the tumor (NAT), to liver cancer tissues.115 Our initial findings in an azoxymethane (AOM)/dextran sodium sulphate (DSS)-induced mouse model for cancer-initiating cells (CICs) indicate a gradual elevation in FKBP11 expression within normal intestinal epithelial cells, IBD colon tissues, and CIC colon tissues. This underscores FKBP11's role in the chronic viral hepatitis-driven carcinogenesis and its possible involvement in the inflammation-carcinogenesis continuum leading to hepatitis-liver cancer. FKBP11 exhibits a strong association with CIC development within the cytoplasm and nucleus, yet the precise molecular underpinnings remain uncharted. As such, there is a crucial imperative to elucidate the intricate molecular mechanism through which FKBP11 propels CIC development

FKBP11 potentially exerts regulatory control over CICs via c-Myc-associated signaling cascades. C-Myc, a recognized nuclear transcription factor, is instrumental in both normal cellular physiological functions and the emergence of malignancies. Immunoprecipitation assays have indicated potential interaction between c-Myc and FKBP proteins, pointing to a conceivable interaction with the FKBP family.116,117 Recent investigations have unveiled c-Myc's role in mediating E-selectin ligand expression and attenuating MUC2 expression in colon cancer cells during the process of epithelial-mesenchymal transition (EMT) prompted by EGF stimulation.118 Furthermore, c-Myc has been observed to collaborate with ERS mechanisms to foster tumorigenesis. In human lymphoma cells, heightened c-Myc expression triggers activation of the pivotal unfolded protein response (UPR) pathways, IREK and IRE1α, diminishing tumor cell ERS, thereby bolstering prolific protein synthesis, inhibiting cell apoptosis, and expediting cell proliferation and malignant transformation. Conversely, therapeutic interventions aimed at UPR modulation can hinder malignancy stemming from c-Myc expression.119 C-Myc holds potential significance as a gene integral to CIC dynamics and possibly engages in the context of IBD and its tumorigenesis. Its expression tends to be suppressed during colonic inflammation, yet emerges as overexpressed in CIC-derived adenocarcinomas.120,121 Furthermore, MUC5AC serves as an epicenter for the β-catenin/c-Myc interplay, culminating in the promotion of glutamine dependency during the resistance to chemotherapy in pancreatic cancer.122

Elevated levels of IL-6 during the course of IBD facilitate the upregulation of c-Myc protein expression through an IRES-dependent translation pathway. Concurrently, heightened c-Myc levels trigger ribosome biosynthesis via MDM2-mediated proteasomal degradation of p53, thereby fostering the transformative malignancy of cells.123 In accordance with this, in the murine model of CICs, the expression of c-Myc gradually escalates with disease progression, primarily localizing within the cytoplasm and nucleus. Amid chronic inflammation stimulation, the role and impact of the ERS protein FKBP11 on the proto-oncogene c-Myc warrant investigation. Recent research underscores that the spatial conformation of c-Myc protein can modulate both its protein stability and transcriptional activity, and within this process, Pin1, a member of the PPIase family, emerges as a pivotal player.124 Pin1, characterized by its conservation, specificity, and phosphorylation-directed PPIase activity, orchestrates target protein stability modulation by reshaping their spatial conformation during the cell cycle. In diverse tumor tissues, elevated expressions of both Pin1 and c-Myc have been observed, potentially attributable to disruptions in the ubiquitin-proteasome pathway that bolster c-Myc stability. Additionally, heightened Pin1 levels potentiate c-Myc's transcriptional activity akin to a molecular chaperone.125 Notably, preliminary findings from our research underscore the affiliation between FKBP11 and Pin1 within the same PPIase family. Given FKBP11's capacity to elevate transcription factor expression and exhibit molecular chaperone function, we speculate that FKBP11 operates via a comparable regulatory mechanism as Pin1. Enhanced FKBP11 expression significantly promotes colon cancer cell proliferation and augments Myc's transcriptional activity. Thus, we posit that heightened FKBP11 levels might propel cellular proliferation by governing the stability of c-Myc protein and the transcriptional modulation of downstream target genes.

In summary, synthesizing prior investigations and our preliminary findings, we have put forth a comprehensive model elucidating the mechanism of ERS-mediated inflammation-cancer transition (Fig. 5). Persistent inflammation triggers ERS within the intestinal epithelial cells, leading to the perturbation of cell-adhesion elements, namely E-cadherin (CDH1), and mucins responsible for gel formation (MUC2). This disruption diminishes their capacity to safeguard against bacterial intrusion and infection. Concurrently, ERS heightens the expression of FKBP11, which engages with c-Myc as a molecular chaperone. Through its PPIase activity, FKBP11 orchestrates a reconfiguration of c-Myc's spatial conformation. This conformational adjustment fosters c-Myc's phosphorylation, thereby fueling its oncogenic potential,126 and amplifies c-Myc's stability and transcriptional prowess. ERS-triggered FKBP/c-Myc complex further exerts control over endoplasmic reticulum-ribosome synthesis, while concomitantly repressing p53 expression. These dual actions contribute to heightened cellular proliferation and the evolution of inflammation-cancer transformation. Our ongoing investigations are aimed at empirically validating this hypothesis, delving into the nuanced regulation of the proto-oncogene c-Myc by FKBP11, and exploring aberrant RNA glycosylation as another important direction to decipher the CIC mechanism.127 A deeper comprehension of the molecular underpinnings governing carcinogenesis in inflammatory bowel disease holds the potential to unveil novel clinical targets for the treatment of colorectal cancer.

5. Conclusions

Comprehending the molecular intricacies underpinning cancer emergence due to chronic inflammation holds substantial importance in the realms of cancer diagnosis and treatment. Genetic mutations frequently accompany inflammation-triggered cancers, often inciting oncogenic changes. Chronic inflammation fosters elevated cancer susceptibility by generating bioactive molecules like proinflammatory cytokines from infiltrating cells within the tumor microenvironment. Moreover, it can detrimentally impact mucosal gels on the colorectal epithelium, provoking dysregulation in mucin function and inducing irregular glycosylation. Furthermore, abnormal glycosylation in glycoproteins within human body fluids can potentially serve as diagnostic or prognostic indicators for inflammation and colitis-associated cancers. Molecular assessments have implicated endoplasmic reticulum stress in the process of inflammation-cancer transformation via the PPIase/c-Myc/p53 signaling pathway, potentially paving the way for deeper insights into molecular mechanisms and therapeutic target identification.

Competing financial interests

The authors declare no competing financial interests.

Declarations

Not applicable.

CRediT authorship contribution statement

Xiaotong Wang: Writing – review & editing, Writing – original draft, Funding acquisition, Conceptualization. Yunqiu Shen: Writing – review & editing, Visualization, Resources. Yan Chen: Writing – review & editing, Visualization, Investigation, Conceptualization. Shuang Yang: Writing – review & editing, Writing – original draft, Visualization, Investigation, Funding acquisition, Conceptualization.

Acknowledgements

This research has received financial support from the Soochow University Start-up Fund. We extend our gratitude to the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD), the Jiangsu Science and Technology Plan Funding (BX2022023), the Jiangsu Shuangchuang Boshi Funding (JSSCBS20210697), the Suzhou Medical Innovation Funding (SKJY2021141).

Abbreviations

ADP Adenosine diphosphate

AGP1 α1-acid glycoprotein

AML: Acute myeloid leukemia

AOM Azoxymethane

APP Acute-phase protein

APP Acute-phase protein

CAF Cancer-associated fibroblast

CD Crohn's disease

CD36 Platelet glycoprotein 4

CDH E-cadherin

CHOP C/EBP homologous protein

CIC Colitis-associated cancer

CRC Colorectal cancer

CRP C-reactive protein

DDR DNA damage response

DNMT DNA (cytosine-5)-methyltransferase

DSS Dextran sulphate sodium

EGF Epidermal growth factor

EMT Epithelial-mesenchymal transition

ERS Endoplasmic reticulum stress

FC Fold-changes

FGFR1 Fibroblast growth factor receptor 1

FKBP11 FKBP prolyl isomerase 11

GIT Gastrointestinal tract

GTP Guanosine triphosphate

GWAS Genome-wide association studies

HPRT Hypoxanthine phosphoribosyltransferase

HPRT Hypoxanthine phosphoribosyltransferase

IBD Inflammatory bowel disease

IFIH1 Interferon-induced helicase C domain-containing protein 1

IL-6 Interleukin-6

ILC1 Innate lymphoid cells type 1

IRGM Immunity-related GTPase

LPS Bacterial lipopolysaccharide

LRG1 Leucin-rich α-2 glycoprotein

MD-2 Myeloid differentiation factor 2

MDM2 Murine double minute 2

MDSC Myeloid-derived suppressor cell

MUC2 Mucin 2

NAT Normal tissue adjacent to the tumor

Neu Neutrophil

NO Free radicals

PAX5 Paired box 5

Pin1 Prolyl isomerase pin1

PPlase Peptidyl-prolyl-cis-trans isomerase

RONS Reactive oxygen/nitrogen species

ROS Reactive oxygen species

SAA1 Serum amyloid A

SERPINA3 α1-antichymotrypsin

TAM Tumor-associated macrophage

TCR T cell receptor

Th 1 Type 1 T helper

TLR4 Toll-like receptor 4

TME Tumor microenvironment

TR Tandem repeats

TSG Tumor suppressor gene

UC Ulcerative colitis

UPR Unfolded protein response

VNTR Variable number of tandem re

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.abst.2024.06.002.

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Received 22 March 2024; Received in revised form 6 June 2024; Accepted 16 June 2024

Available online 17 June 2024 2543-1064/© 2024 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Footnote

* Corresponding author. Health Management Center, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China.

** Corresponding author.

E-mail addresses: [email protected] (Y. Chen), [email protected] (S. Yang).

References

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