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. 2015 Dec 3;5:17663.
doi: 10.1038/srep17663.

Multiple Regulation Pathways and Pivotal Biological Functions of STAT3 in Cancer

Free PMC article

Multiple Regulation Pathways and Pivotal Biological Functions of STAT3 in Cancer

Jie Yuan et al. Sci Rep. .
Free PMC article


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.


Figure 1
Figure 1. Multiple regulation pathways of STAT3 in cancer.
Cytokine receptors, especially receptors for IL-6 family cytokines, are the most well-known traditional activators of STAT3. Receptor tyrosine kinases, non-Receptor tyrosine kinases and some serine kinases can also regulate the STAT3 activity. Recently, studies found that GPCRs and TLRs are involved in the regulation of STAT3. Cadherin engagement accompanied with the high level of Rac1/Cdc42 also dramatically regulates STAT3 through activating the NF-κB signal pathway. SOCS inhibits STAT3 signaling via blockade of upstream signaling through interactions with gp130 and JAK family members. Various miRNAs either restrict or enhance STAT3 signaling. PTPases dephosphorylate STAT3 and prevents dimer formation. PIAS proteins directly compete with STAT3 for either binding opportunities with the activating receptor or for dimerization and translocation into the nucleus.
Figure 2
Figure 2. Pivotal biologiccal functions in cancer and inhibitors of STAT3.
STAT3 plays a pivotal role in tumor onset and progression through altering gene expression via epigenetic modification, inducing EMT phenotypes in cancer cells, regulating the tumor microenvironment, and promoting CSCs self-renewal and differentiation. As an ideal target for cancer therapy, lots of indirect or direct inhibitors for STAT3 have been developed recently.

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