STAT3—An Oncogenic Signaling Hub That Drives Stemness
STAT3 is a transcription factor that, when overactivated, becomes an oncogenic signaling hub that promotes stemness, suppresses antitumor immunity, and drives tumor-promoting inflammation.1,2
STAT3 is overactivated in CSCs3
- In normal cells, STAT3 is activated in a strictly regulated and transient process4
- However, when STAT3 signaling is overactivated, it can drive the development and progression of tumors5
- STAT3 is constitutively active in CSCs and may be critical for maintaining their stemness, the ability to self-renew and differentiate3,6
- CSCs are highly tumorigenic with high metastatic potential, and they are more resistant to conventional therapies than non-stem cancer cells in tumors3,7
STAT3 mediates downstream effects that promote stemness3,8
- STAT3 receives upstream activating signals from the interaction of CSC surface receptors with various molecules, including growth factors and proinflammatory cytokines4
- Activated STAT3 translocates into the CSC nucleus9 and participates in crosstalk with other stemness signaling pathways1,10,11
- Thus, STAT3 mediates multiple downstream effects, including increased expression of genes that maintain stemness3,8
STAT3 may suppress antitumor immunity and drive tumor-promoting inflammation12
- STAT3 has been shown to suppress antitumor immunity, particularly by antagonizing the effects of nuclear factor-kappa B (NF-κB) that support both innate and T cell–mediated immune responses12
- STAT3 also drives tumor-promoting inflammation by increasing the expression of proinflammatory cytokines such as IL-62,12
- These cytokines in turn bind to receptors, including CSC surface receptors, resulting in an inflammatory positive feedback loop2,12
- Hajimoradi M, Mohammad Hassan Z, Ebrahimi M, et al. STAT3 is overactivated in gastric cancer stem-like cells. Cell J. 2016;17(4):617-628.
- Yuan J, Zhang F, Niu R. Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. Sci Rep. 2015;5:17663.
- Cafferkey C, Chau I. Novel STAT 3 inhibitors for treating gastric cancer. Expert Opin Investig Drugs. 2016;25(9):1023-1031.
- Siveen KS, Sikka S, Surana R, et al. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta. 2014;1845(2):136-154.
- Wang S-W, Sun Y-M. The IL-6/JAK/STAT3 pathway: potential therapeutic strategies in treating colorectal cancer [Review]. Int J Oncol. 2014;44(4):1032-1040.
- Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111.
- Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015;112(6):1839-1844.
- Kamran MZ, Patil P, Gude RP. Role of STAT3 in cancer metastasis and translational advances. Biomed Res Int. 2013;2013:421821. doi:10.1155/2013/421821.
- Huang S. Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications. Clin Cancer Res. 2007;13(5):1362-1366.
- Garner JM, Fan M, Yang CH, et al. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB signaling in glioblastoma cancer stem cells regulates the Notch pathway. J Biol Chem. 2013;288(36):26167-26176.
- Pramanik KC, Fofaria NM, Gupta P, Ranjan A, Kim S-H, Srivastava SK. Inhibition of β-catenin signaling suppresses pancreatic tumor growth by disrupting nuclear β-catenin/TCF-1 complex: critical role of STAT-3. Oncotarget. 2015;6(13):11561-11574.
- Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9(11):798-809.