Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Dec 3;5:17663.
doi: 10.1038/srep17663.

Multiple Regulation Pathways and Pivotal Biological Functions of STAT3 in Cancer

Affiliations
Free PMC article
Review

Multiple Regulation Pathways and Pivotal Biological Functions of STAT3 in Cancer

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

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.

Figures

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.

Similar articles

See all similar articles

Cited by 65 articles

See all "Cited by" articles

References

    1. Timofeeva O. A. et al. . STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain. Proc Natl Acad Sci USA 110, 1267–1272, doi: 10.1073/pnas.1211805110 (2013). - DOI - PMC - PubMed
    1. Li J. et al. . STAT3 acetylation-induced promoter methylation is associated with downregulation of the ARHI tumor-suppressor gene in ovarian cancer. Oncol Rep 30, 165–170, doi: 10.3892/or.2013.2414 (2013). - DOI - PubMed
    1. Lee H. et al. . Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation. Proc Natl Acad Sci USA 109, 7765–7769, doi: 10.1073/pnas.1205132109 (2012). - DOI - PMC - PubMed
    1. Zheng L. et al. . Angiotensin II in atrial structural remodeling: the role of Ang II/JAK/STAT3 signaling pathway. Am J Transl Res 7, 1021–1031 (2015). - PMC - PubMed
    1. Smith G. S., Kumar A. & Saba J. D. Sphingosine Phosphate Lyase Regulates Murine Embryonic Stem Cell Proliferation and Pluripotency through an S1P/STAT3 Signaling Pathway. Biomolecules 3, 351–368, doi: 10.3390/biom3030351 (2013). - DOI - PMC - PubMed

Publication types

Substances

LinkOut - more resources

Feedback