Abstract
STAT3 is both a transcription activator and an oncogene that is tightly regulated under normal physiological conditions. However, abundant evidence indicates that STAT3 is persistently activated in several cancers, with a crucial position in tumor onset and progression. In addition to its traditional role in cancer cell proliferation, invasion, and migration, STAT3 also promotes cancer through altering gene expression via epigenetic modification, inducing epithelial–mesenchymal transition (EMT) phenotypes in cancer cells, regulating the tumor microenvironment, and promoting cancer stem cells (CSCs) self-renewal and differentiation. STAT3 is regulated not only by the canonical cytokines and growth factors, but also by the G-protein-coupled receptors, cadherin engagement, Toll-like receptors (TLRs), and microRNA (miRNA). Despite the presence of diverse regulators and pivotal biological functions in cancer, no effective therapeutic inventions are available for inhibiting STAT3 and acquiring potent antitumor effects in the clinic. An improved understanding of the complex roles of STAT3 in cancer is required to achieve optimal therapeutic effects.
Highlights
Prolonged activation of STAT3 leads to low expression of let-7 and miR-200 coupled with the upregulation of ZEB1 in OSM-triggered epithelial–mesenchymal transition (EMT), which contributes to the acquisition of the mesenchymal phenotype and invasive capability as well as promotion of breast cancer progression[23]. These findings suggest that STAT3 responds to the integrating signals from multiple extracellular stimuli that influence the EMT phenotype, regulates the level of EMT-related transcription factors, and enhances the cancer cell abilities of invasion, metastasis
Cancer-associated fibroblasts (CAFs) can promote cancer progression via remodeling the ECM, induction of angiogenesis, recruitment of inflammatory cells, and directly stimulating cancer cell proliferation via the secretion of growth factors and mesenchymal–epithelial cell interactions, which are mainly regulated by the IL-6–STAT3–Twist signaling pathway by upregulating the expression of CXCL1260, a Twist target gene associated with the regulation of the CAF phenotype
STAT3 is an ideal target of cancer therapy because of its multiple regulatory pathways and pivotal biological functions in cancer; various inhibitors targeting STAT3 have been developed for cancer therapy, no candidate compounds are potent enough to provide beneficial therapeutic effects for cancer patients
Summary
The persistent phosphorylated form of STAT3 has been found in several cancers and leads to gene expression promoting cell proliferation and resistance to apoptosis, as well as tumor angiogenesis, invasion, and migration, unphosphorylated STAT3 acts as a weak but potentially biologically relevant transcription factor that can activate a series of STAT3 target genes[44,45] through direct binding to a responsive GAS promoter and promotes the development of cancer. The epigenetic gene silencing effect of gene promoter region mediated through the CpG methylation by DNA methyltransferase 1 (DNMT1) and other members of the DNMT family have key roles in the inhibition of tumor-suppressor gene expression in cancer cells.
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