Revisiting STAT3 Signalling in Cancer: New and Unexpected Biological Functions

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2014 Oct 25

PMID 25342631

Citations 1108

Authors

Hua Yu

Heehyoung Lee

Andreas Herrmann

Ralf Buettner

Richard Jove

Affiliations

Soon will be listed here.

Abstract

The Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins, particularly STAT3, are among the most promising new targets for cancer therapy. In addition to interleukin-6 (IL-6) and its family members, multiple pathways, including G-protein-coupled receptors (GPCRs), Toll-like receptors (TLRs) and microRNAs were recently identified to regulate JAK-STAT signalling in cancer. Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK-STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche. In addition to its established role as a transcription factor in cancer, STAT3 regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms. Newly identified regulators and functions of JAK-STAT3 in tumours are important targets for potential therapeutic strategies in the treatment of cancer.

Citing Articles

The clinical significance of T-cell regulation in hypertension treatment.

Fu M, Lv M, Guo J, Mei A, Qian H, Yang H Front Immunol. 2025; 16:1550206.

PMID: 40079010 PMC: 11897580. DOI: 10.3389/fimmu.2025.1550206.

Targeting STAT3 for Cancer Therapy: Focusing on Y705, S727, or Dual Inhibition?.

Berkley K, Zalejski J, Sharma A Cancers (Basel). 2025; 17(5).

PMID: 40075607 PMC: 11898704. DOI: 10.3390/cancers17050755.

Asiaticoside-nitric oxide synergistically accelerate diabetic wound healing by regulating key metabolites and SRC/STAT3 signaling.

Mu X, Chen J, Zhu H, Deng J, Wu X, He W Burns Trauma. 2025; 13:tkaf009.

PMID: 40066291 PMC: 11891651. DOI: 10.1093/burnst/tkaf009.

The RNA binding protein CARHSP1 facilitates tumor growth, metastasis and immune escape by enhancing IL-17RA mRNA stabilization in prostate cancer.

Jiang Y, Wang Y, Xue K, Ma J, Xu S, Wang K Cell Biosci. 2025; 15(1):33.

PMID: 40055805 PMC: 11889941. DOI: 10.1186/s13578-025-01371-4.

Enhancement of radio-sensitivity by inhibition of Janus kinase signaling with oclacitinib in canine tumor cell lines.

Owaki R, Hosoya K, Deguchi T, Konnai S, Maekawa N, Okagawa T Mol Ther Oncol. 2025; 33(1):200946.

PMID: 40051504 PMC: 11883359. DOI: 10.1016/j.omton.2025.200946.

References

Gupta M, Han J, Stenson M, Maurer M, Wellik L, Hu G . Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation. Blood. 2012; 119(12):2844-53. PMC: 3327462. DOI: 10.1182/blood-2011-10-388538. View

Putoczki T, Thiem S, Loving A, Busuttil R, Wilson N, Ziegler P . Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell. 2013; 24(2):257-71. DOI: 10.1016/j.ccr.2013.06.017. View

Rosen H, Goetzl E . Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol. 2005; 5(7):560-70. DOI: 10.1038/nri1650. View

Zhang L, Alizadeh D, Van Handel M, Kortylewski M, Yu H, Badie B . Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. Glia. 2009; 57(13):1458-67. DOI: 10.1002/glia.20863. View

Peterson L, Artis D . Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014; 14(3):141-53. DOI: 10.1038/nri3608. View

Su Y, Lai H, Chang Y, Chen G, Lee J . Direct reprogramming of stem cell properties in colon cancer cells by CD44. EMBO J. 2011; 30(15):3186-99. PMC: 3160185. DOI: 10.1038/emboj.2011.211. View

Paugh B, Bryan L, Paugh S, Wilczynska K, Alvarez S, Singh S . Interleukin-1 regulates the expression of sphingosine kinase 1 in glioblastoma cells. J Biol Chem. 2008; 284(6):3408-17. PMC: 2635028. DOI: 10.1074/jbc.M807170200. View

Stark G, Kerr I, Williams B, Silverman R, Schreiber R . How cells respond to interferons. Annu Rev Biochem. 1998; 67:227-64. DOI: 10.1146/annurev.biochem.67.1.227. View

Schafer Z, Brugge J . IL-6 involvement in epithelial cancers. J Clin Invest. 2007; 117(12):3660-3. PMC: 2096452. DOI: 10.1172/JCI34237. View

10.

Noto H, Goto A, Tsujimoto T, Noda M . Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One. 2012; 7(3):e33411. PMC: 3308971. DOI: 10.1371/journal.pone.0033411. View

11.

Pitman M, Emery B, Binder M, Wang S, Butzkueven H, Kilpatrick T . LIF receptor signaling modulates neural stem cell renewal. Mol Cell Neurosci. 2004; 27(3):255-66. DOI: 10.1016/j.mcn.2004.07.004. View

12.

Chen G, Zhao Z, Zhou H, Liu Y, Yang H . Systematic analysis of microRNA involved in resistance of the MCF-7 human breast cancer cell to doxorubicin. Med Oncol. 2009; 27(2):406-15. DOI: 10.1007/s12032-009-9225-9. View

13.

Zhong Z, Wen Z, Darnell Jr J . Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994; 264(5155):95-8. DOI: 10.1126/science.8140422. View

14.

Grivennikov S . IL-11: a prominent pro-tumorigenic member of the IL-6 family. Cancer Cell. 2013; 24(2):145-7. PMC: 3855069. DOI: 10.1016/j.ccr.2013.07.018. View

15.

Wang L, Yi T, Kortylewski M, Pardoll D, Zeng D, Yu H . IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009; 206(7):1457-64. PMC: 2715087. DOI: 10.1084/jem.20090207. View

16.

Zhang Q, Raje V, Yakovlev V, Yacoub A, Szczepanek K, Meier J . Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727. J Biol Chem. 2013; 288(43):31280-8. PMC: 3829438. DOI: 10.1074/jbc.M113.505057. View

17.

Visentin B, Vekich J, Sibbald B, Cavalli A, Moreno K, Matteo R . Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell. 2006; 9(3):225-38. DOI: 10.1016/j.ccr.2006.02.023. View

18.

Marzec M, Halasa K, Kasprzycka M, Wysocka M, Liu X, Tobias J . Differential effects of interleukin-2 and interleukin-15 versus interleukin-21 on CD4+ cutaneous T-cell lymphoma cells. Cancer Res. 2008; 68(4):1083-91. DOI: 10.1158/0008-5472.CAN-07-2403. View

19.

Guryanova O, Wu Q, Cheng L, Lathia J, Huang Z, Yang J . Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3. Cancer Cell. 2011; 19(4):498-511. PMC: 3076106. DOI: 10.1016/j.ccr.2011.03.004. View

20.

Timofeeva O, Chasovskikh S, Lonskaya I, Tarasova N, Khavrutskii L, Tarasov S . Mechanisms of unphosphorylated STAT3 transcription factor binding to DNA. J Biol Chem. 2012; 287(17):14192-200. PMC: 3340179. DOI: 10.1074/jbc.M111.323899. View