Multiple regulation pathways and pivotal biological functions of STAT3 in cancer

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.