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Introduction
Gastric cancer (GC) is one of the most common causes of cancer-associated mortality worldwide and is a major health problem in China with an increasing incidence and mortality rate according to a survey in 2015 (1,2). Although advances have been made in the detection and clinical treatment of GC in previous decades, marked variation in survival rates are found between patients diagnosed at different tumor stages. Patients diagnosed during the later stage often have metastatic disease and are no longer able to receive surgical treatment, leaving chemotherapy as the only available option (3). However, chemotherapy is often associated with a low response rate, high toxicity and drug resistance in a large number of patients (4–6). Therefore, there is an urgency for identifying and developing novel compounds to optimize therapeutic options and improve the prognosis of patients with GC.
Signal transducer and activator of transcription 3 (STAT3) is the most studied member of the STAT family and is constitutively activated in various malignancies, including GC (7). Under normal physiological conditions, cells exhibit transient STAT3 phosphorylation, which lasts for only a relatively short period of time; however, once the tumor-related signaling pathways are dysregulated, this process becomes constitutive (8). Following activation, STAT3 undergoes phosphorylation-induced dimerization, nuclear translocation and binding to its target genes, leading to the transcriptional activation of downstream target genes that regulate tumor cell proliferation and progression (3,9). There is substantial evidence demonstrating that the phosphorylation of STAT3 is abnormally activated in GC and that the constitutive activation of STAT3 is positively correlated with a poor prognosis and metastasis, indicating that it may serve as a negative prognostic factor (7,10–12). As a consequence, inhibitors targeting the activation of STAT3 offer promise in suppressing cancer proliferation and mobility and are being widely investigated in GC and several other types of cancer that contain activated STAT3 (13,14). However, the majority of STAT3 inhibitors fail to demonstrate satisfactory ability to suppress tumor growth and/or have high toxicity (15). Therefore, it remains important to identify novel inhibitors of STAT3 activation that are effective in treating GC, while producing minimal side effects.
In addition, the dysregulation of mitogen-activated protein kinase (MAPK) signaling is closely associated with cell growth, progression and apoptosis. The three most widely studied MAPKs are extracellular...