STAT3 Pathway

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

EMT=epithelial-mesenchymal transition.

  • 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

IL=interleukin.

  • 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

References

  1. 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.
  2. Yuan J, Zhang F, Niu R. Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. Sci Rep. 2015;5:17663.
  3. Cafferkey C, Chau I. Novel STAT 3 inhibitors for treating gastric cancer. Expert Opin Investig Drugs. 2016;25(9):1023-1031.
  4. 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.
  5. 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.
  6. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.