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Revisiting STAT3 signalling in cancer: new and unexpected biological functions

Key Points

  • The Janus kinases (JAKs) are major activators of signal transducer and activator of transcription (STAT) proteins. JAK–STAT3 signalling is crucial for cancer development in both tumour cells and the tumour microenvironment, and both JAK and STAT3 have emerged as important targets for cancer treatment.

  • Interleukin-6 (IL-6) and several other members of the IL-6 family have a prominent role in JAK–STAT3 activation in cancer. Antibodies that target IL-6 are currently in clinical trials for cancer treatment. However, owing to a multitude of cytokines, growth factors and many other molecules that activate JAK–STAT3, blocking IL-6 and its family members alone is not likely to be sufficient for cancer treatment.

  • Several G-protein-coupled receptors (GPCRs) are found to activate STAT3 through JAKs, leading to cancer progression. GPCRs are more readily druggable than STAT3, which is a transcription factor and therefore difficult to target because it is mostly in the nucleus and lacks enzymatic activity.

  • Although Toll-like receptors (TLRs) are usually associated with immune activation, several of them are overexpressed and could promote cancer via the JAK–STAT3 pathway in both immune cells and tumour cells. The synthetic ligand of TLR9A, CpG oligonucleotide, when linked to small interfering RNA (siRNA) against STAT3, has been shown to be an effective approach to deliver RNA into both immune cells and tumour cells. The CpG–STAT3 siRNA is now poised to enter clinical trials for cancer treatment.

  • Some microRNAs that interact with the JAK–STAT3 pathway are emerging as having crucial roles in regulating cancer-promoting inflammation and oncogenesis. Appropriate microRNAs that can block the JAK–STAT3 pathway could potentially be developed as inhibitors of this pathway with clinical application.

  • Although STAT3 is well known as a transcription factor that defines a gene expression programme in cancer, recent studies have identified surprising roles of STAT3 in mitochondria in cancer. Importantly, STAT3 also contributes to cancer progression by DNA methylation and chromatin topological modulation.


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.

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Figure 1: Pathways activating JAK–STAT3 signalling in cancer.
Figure 2: STAT3–microRNA regulatory circuits.
Figure 3: Newly identified roles of JAK–STAT3 in cancer.


  1. 1

    Taga, T. et al. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58, 573–581 (1989).

    CAS  PubMed  Google Scholar 

  2. 2

    Darnell, J. E., Kerr, I. M. & Stark, G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994).

    CAS  Google Scholar 

  3. 3

    Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    CAS  PubMed  Google Scholar 

  4. 4

    Buettner, R., Mora, L. B. & Jove, R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin. Cancer Res. 8, 945–954 (2002).

    CAS  PubMed  Google Scholar 

  5. 5

    Yu, H. & Jove, R. The STATs of cancer—new molecular targets come of age. Nature Rev. Cancer 4, 97–105 (2004).

    CAS  Google Scholar 

  6. 6

    Haura, E. B., Turkson, J. & Jove, R. Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer. Nature Clin. Pract. Oncol. 2, 315–324 (2005).

    CAS  Google Scholar 

  7. 7

    Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nature Rev. Cancer 9, 798–809 (2009).

    CAS  Google Scholar 

  8. 8

    Bromberg, J. & Darnell, J. E. Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468–2473 (2000).

    CAS  PubMed  Google Scholar 

  9. 9

    Herrmann, A. et al. Targeting Stat3 in the myeloid compartment drastically improves the in vivo antitumor functions of adoptively transferred T cells. Cancer Res. 70, 7455–7464 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Kortylewski, M. & Yu, H. Role of Stat3 in suppressing anti-tumor immunity. Curr. Opin. Immunol. 20, 228–233 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Kujawski, M. et al. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J. Clin. Invest. 118, 3367–3377 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Wang, L. et al. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J. Exp. Med. 206, 1457–1464 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Kortylewski, M. et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nature Med. 11, 1314–1321 (2005).

    CAS  PubMed  Google Scholar 

  14. 14

    Yu, H., Kortylewski, M. & Pardoll, D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nature Rev. Immunol. 7, 41–51 (2007).

    CAS  Google Scholar 

  15. 15

    Zhang, L. et al. Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. Glia 57, 1458–1467 (2009).

    PubMed  Google Scholar 

  16. 16

    Priceman, S. J. et al. Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance. Proc. Natl Acad. Sci. USA 110, 13079–13084 (2013). This is the first demonstration that STAT3 in T cells promotes obesity-induced inflammation and insulin resistance, providing a new link between diabetes and cancer.

    CAS  PubMed  Google Scholar 

  17. 17

    Deng, J. et al. S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer Cell 21, 642–654 (2012). This paper demonstrates a role of STAT3 in promoting myeloid cell survival and proliferation in future metastatic sites, thereby facilitating tumour metastasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010). This is the first direct evidence linking obesity with inflammation-associated tumorigenesis, in part mediated by the IL-6–STAT3 pathway.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Carro, M. S. et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature 463, 318–325 (2010).

    CAS  PubMed  Google Scholar 

  20. 20

    Marotta, L. L. et al. The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24 stem cell-like breast cancer cells in human tumors. J. Clin. Invest. 121, 2723–2735 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Schroeder, A. et al. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res. 74, 1227–1237 (2014). This paper provides evidence for a crucial role of activated STAT3 signalling in promoting CSCs and resistance to therapy in prostate cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Hossain, D. M. et al. Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity. Blood 123, 15–25 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Kortylewski, M. et al. Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy. Cancer Res. 69, 2497–2505 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Eyking, A. et al. Toll-like receptor 4 variant D299G induces features of neoplastic progression in Caco-2 intestinal cells and is associated with advanced human colon cancer. Gastroenterology 141, 2154–2165 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Tye, H. et al. STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell 22, 466–478 (2012). This is the first report describing the role of TLRs in oncogenesis without tumour inflammation.

    CAS  PubMed  Google Scholar 

  26. 26

    Herrmann, A. et al. TLR9 is critical for glioma stem cell maintenance and targeting. Cancer Res. 74, 5218–5228 (2014). This is the first demonstration that TLR9 forms a feed-forward loop with STAT3 that is crucial for GSC maintenance. The overexpression of TLR9 on the CSCs allows their targeting by CpG–STAT3 siRNA.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Iliopoulos, D., Hirsch, H. A. & Struhl, K. An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009). This is the first paper describing the importance of epigenetic regulation in promoting inflammation and cancer, which is mediated by the IL-6–STAT3 pathway.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Guo, L. et al. Stat3-coordinated Lin-28-let-7-HMGA2 and miR-200-ZEB1 circuits initiate and maintain oncostatin M-driven epithelial-mesenchymal transition. Oncogene 32, 5272–5282 (2013).

    CAS  PubMed  Google Scholar 

  29. 29

    Sugimura, K. et al. Let-7 expression is a significant determinant of response to chemotherapy through the regulation of IL-6/STAT3 pathway in esophageal squamous cell carcinoma. Clin. Cancer Res. 18, 5144–5153 (2012).

    CAS  PubMed  Google Scholar 

  30. 30

    Navarro, A. et al. Regulation of JAK2 by miR-135a: prognostic impact in classic Hodgkin lymphoma. Blood 114, 2945–2951 (2009).

    CAS  PubMed  Google Scholar 

  31. 31

    Du, L. et al. miR-337-3p and its targets STAT3 and RAP1A modulate taxane sensitivity in non-small cell lung cancers. PLoS ONE 7, e39167 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Lee, H. et al. STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nature Med. 16, 1421–1428 (2010). This report provides the first demonstration that a lipid metabolite receptor, S1PR1, which is also a GPCR, activates STAT3 through a feed-forward loop in tumours.

    CAS  PubMed  Google Scholar 

  33. 33

    Xin, H. et al. G-protein-coupled receptor agonist BV8/prokineticin-2 and STAT3 protein form a feed-forward loop in both normal and malignant myeloid cells. J. Biol. Chem. 288, 13842–13849 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Catlett-Falcone, R. et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10, 105–115 (1999).

    CAS  PubMed  Google Scholar 

  35. 35

    Zhong, Z., Wen, Z. & Darnell, J. E. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264, 95–98 (1994).

    CAS  PubMed  Google Scholar 

  36. 36

    Heinrich, P. C. et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 374, 1–20 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Putoczki, T. L. et al. Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell 24, 257–271 (2013).

    CAS  PubMed  Google Scholar 

  38. 38

    Grivennikov, S. I. IL-11: a prominent pro-tumorigenic member of the IL-6 family. Cancer Cell 24, 145–147 (2013).

    CAS  PubMed  Google Scholar 

  39. 39

    Silver, J. S. & Hunter, C. A. gp130 at the nexus of inflammation, autoimmunity, and cancer. J. Leukoc. Biol. 88, 1145–1156 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Jones, S. A., Scheller, J. & Rose-John, S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J. Clin. Invest. 121, 3375–3383 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Atsumi, T. et al. A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J. Exp. Med. 196, 979–990 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Putoczki, T. & Ernst, M. More than a sidekick: the IL-6 family cytokine IL-11 links inflammation to cancer. J. Leukoc. Biol. 88, 1109–1117 (2010).

    CAS  PubMed  Google Scholar 

  43. 43

    White, U. A. & Stephens, J. M. The gp130 receptor cytokine family: regulators of adipocyte development and function. Curr. Pharm. Des. 17, 340–346 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Bollrath, J. et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15, 91–102 (2009).

    CAS  Google Scholar 

  46. 46

    Schiechl, G. et al. Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80+CD11bhighGr1low macrophages. J. Clin. Invest. 121, 1692–1708 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Zhang, L. et al. Role of the microenvironment in mantle cell lymphoma: IL-6 is an important survival factor for the tumor cells. Blood 120, 3783–3792 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Schafer, Z. T. & Brugge, J. S. IL-6 involvement in epithelial cancers. J. Clin. Invest. 117, 3660–3663 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Sansone, P. et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J. Clin. Invest. 117, 3988–4002 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Pine, S. R. et al. Increased levels of circulating interleukin 6, interleukin 8, C-reactive protein, and risk of lung cancer. J. Natl Cancer Inst. 103, 1112–1122 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Nakashima, J. et al. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin. Cancer Res. 6, 2702–2706 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Chang, Q. et al. The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia 15, 848–862 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Bromberg, J. & Wang, T. C. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 15, 79–80 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Hu, B. et al. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc. Natl Acad. Sci. USA 110, 9862–9867 (2013).

    CAS  Google Scholar 

  55. 55

    Matsumoto, S. et al. Essential roles of IL-6 trans-signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor derived from lamina propria macrophages, on the development of colitis-associated premalignant cancer in a murine model. J. Immunol. 184, 1543–1551 (2010).

    CAS  PubMed  Google Scholar 

  56. 56

    Ernst, M. et al. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J. Clin. Invest. 118, 1727–1738 (2008). This report demonstrates the crucial role of STAT3 and STAT1 in mediating IL-11-dependent tumorigenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Corcoran, R. B. et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 71, 5020–5029 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Liu, S. C. et al. Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance. J. Clin. Invest. 123, 5269–5283 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Penuelas, S. et al. TGF-β increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15, 315–327 (2009).

    CAS  PubMed  Google Scholar 

  60. 60

    Reynaud, D. et al. IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell 20, 661–673 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Ancrile, B., Lim, K. H. & Counter, C. M. Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev. 21, 1714–1719 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Szabo-Fresnais, N., Lefebvre, F., Germain, A., Fischmeister, R. & Pomerance, M. A new regulation of IL-6 production in adult cardiomyocytes by β-adrenergic and IL-1 β receptors and induction of cellular hypertrophy by IL-6 trans-signalling. Cell Signal. 22, 1143–1152 (2010).

    CAS  PubMed  Google Scholar 

  63. 63

    Lu, R., Kujawski, M., Pan, H. & Shively, J. E. Tumor angiogenesis mediated by myeloid cells is negatively regulated by CEACAM1. Cancer Res. 72, 2239–2250 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Shojaei, F., Singh, M., Thompson, J. D. & Ferrara, N. Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc. Natl Acad. Sci. USA 105, 2640–2645 (2008).

    CAS  PubMed  Google Scholar 

  65. 65

    Shojaei, F. et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450, 825–831 (2007).

    CAS  Google Scholar 

  66. 66

    Rosen, H. & Goetzl, E. J. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nature Rev. Immunol. 5, 560–570 (2005).

    CAS  Google Scholar 

  67. 67

    Rivera, J., Proia, R. L. & Olivera, A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nature Rev. Immunol. 8, 753–763 (2008).

    CAS  Google Scholar 

  68. 68

    Maceyka, M., Harikumar, K. B., Milstien, S. & Spiegel, S. Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol. 22, 50–60 (2012).

    CAS  PubMed  Google Scholar 

  69. 69

    Visentin, B. et al. Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 9, 225–238 (2006).

    CAS  Google Scholar 

  70. 70

    Kawamori, T. et al. Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. 23, 405–414 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Sarkar, S. et al. Sphingosine kinase 1 is required for migration, proliferation and survival of MCF-7 human breast cancer cells. FEBS Lett. 579, 5313–5317 (2005).

    CAS  PubMed  Google Scholar 

  72. 72

    Liu, Y. et al. S1PR1 is an effective target to block STAT3 signaling in activated B cell-like diffuse large B-cell lymphoma. Blood 120, 1458–1465 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Ponnusamy, S. et al. Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance. Future Oncol. 6, 1603–1624 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Nava, V. E., Hobson, J. P., Murthy, S., Milstien, S. & Spiegel, S. Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells. Exp. Cell Res. 281, 115–127 (2002).

    CAS  PubMed  Google Scholar 

  75. 75

    Spiegel, S. & Milstien, S. The outs and the ins of sphingosine-1-phosphate in immunity. Nature Rev. Immunol. 11, 403–415 (2011).

    CAS  Google Scholar 

  76. 76

    Liang, J. et al. Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell 23, 107–120 (2013). This is a strong demonstration of the role of the S1P–STAT3–NF-κB pathway in inducing inflammation and colitis-associated cancer development.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Priceman, S. J. et al. S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3. Cell Rep. 6, 992–999 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Paugh, B. S. et al. Interleukin-1 regulates the expression of sphingosine kinase 1 in glioblastoma cells. J. Biol. Chem. 284, 3408–3417 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Miller, A. V., Alvarez, S. E., Spiegel, S. & Lebman, D. A. Sphingosine kinases and sphingosine-1-phosphate are critical for transforming growth factor β-induced extracellular signal-regulated kinase 1 and 2 activation and promotion of migration and invasion of esophageal cancer cells. Mol. Cell. Biol. 28, 4142–4151 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Li, Q. F. et al. Sphingosine kinase-1 mediates BCR/ABL-induced upregulation of Mcl-1 in chronic myeloid leukemia cells. Oncogene 26, 7904–7908 (2007).

    CAS  PubMed  Google Scholar 

  81. 81

    Dayon, A. et al. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival. PLoS ONE 4, e8048 (2009).

    PubMed  PubMed Central  Google Scholar 

  82. 82

    Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).

    CAS  Google Scholar 

  83. 83

    Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nature Immunol. 5, 713–720 (2004).

    CAS  Google Scholar 

  84. 84

    Darnell, J. E. Jr Transcription factors as targets for cancer therapy. Nature Rev. Cancer 2, 740–749 (2002).

    CAS  Google Scholar 

  85. 85

    Liu, C. et al. TLR4 knockout protects mice from radiation-induced thymic lymphoma by downregulation of IL6 and miR-21. Leukemia 25, 1516–1519 (2011).

    CAS  PubMed  Google Scholar 

  86. 86

    Ochi, A. et al. Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. J. Clin. Invest. 122, 4118–4129 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Lowe, E. L. et al. Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer. PLoS ONE 5, e13027 (2010).

    PubMed  PubMed Central  Google Scholar 

  88. 88

    Wang, C. et al. TLR9 expression in glioma tissues correlated to glioma progression and the prognosis of GBM patients. BMC Cancer 10, 415–425 (2010).

    PubMed  PubMed Central  Google Scholar 

  89. 89

    Wild, C. A. et al. Toll-like receptors in regulatory T cells of patients with head and neck cancer. Arch. Otolaryngol. Head Neck Surg. 136, 1253–1259 (2010).

    PubMed  Google Scholar 

  90. 90

    Sullivan, N. J. et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28, 2940–2947 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Tsang, W. P. & Kwok, T. T. Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3. Apoptosis 13, 1215–1222 (2008).

    CAS  PubMed  Google Scholar 

  92. 92

    Yang, N. et al. MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. Cancer Res. 68, 10307–10314 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Chen, G. Q., Zhao, Z. W., Zhou, H. Y., Liu, Y. J. & Yang, H. J. Systematic analysis of microRNA involved in resistance of the MCF-7 human breast cancer cell to doxorubicin. Med. Oncol. 27, 406–415 (2010).

    CAS  PubMed  Google Scholar 

  94. 94

    Xin, F. et al. Computational analysis of microRNA profiles and their target genes suggests significant involvement in breast cancer antiestrogen resistance. Bioinformatics 25, 430–434 (2009).

    CAS  PubMed  Google Scholar 

  95. 95

    Yang, X. et al. MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting IL-6-Stat3 pathway. Hepatology 58, 158–170 (2013).

    CAS  PubMed  Google Scholar 

  96. 96

    Zhang, M. et al. Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. J. Immunol. 186, 4716–4724 (2011).

    CAS  PubMed  Google Scholar 

  97. 97

    Fabbri, M. et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc. Natl Acad. Sci. USA 109, E2110–E2116 (2012).

    CAS  PubMed  Google Scholar 

  98. 98

    Zhuang, G. et al. Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J. 31, 3513–3523 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Zhang, W. et al. Myeloid clusters are associated with a pro-metastatic environment and poor prognosis in smoking-related early stage non-small cell lung cancer. PLoS ONE 8, e65121 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Fenton, J. I. & Birmingham, J. M. Adipokine regulation of colon cancer: adiponectin attenuates interleukin-6-induced colon carcinoma cell proliferation via STAT-3. Mol. Carcinog. 49, 700–709 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Noto, H., Goto, A., Tsujimoto, T. & Noda, M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS ONE 7, e33411 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Franciosi, M. et al. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS ONE 8, e71583 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Buzzai, M. et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67, 6745–6752 (2007).

    CAS  PubMed  Google Scholar 

  104. 104

    Deng, X.-S. et al. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle 11, 367–376 (2012).

    CAS  PubMed  Google Scholar 

  105. 105

    Hirsch, H. A., Iliopoulos, D., Tsichlis, P. N. & Struhl, K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69, 7507–7511 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Hirsch, H. A., Iliopoulos, D. & Struhl, K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc. Natl Acad. Sci. USA 110, 972–977 (2013).

    CAS  PubMed  Google Scholar 

  107. 107

    Willyard, C. Stem cells: bad seeds. Nature 498, S12–13 (2013).

    CAS  PubMed  Google Scholar 

  108. 108

    Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).

    CAS  Google Scholar 

  109. 109

    Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730–737 (1997).

    CAS  PubMed  Google Scholar 

  110. 110

    Magee, J. A., Piskounova, E. & Morrison, S. J. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21, 283–296 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature Rev. Cancer 8, 755–768 (2008).

    CAS  Google Scholar 

  112. 112

    Clarke, M. F. & Fuller, M. Stem cells and cancer: two faces of eve. Cell 124, 1111–1115 (2006).

    CAS  PubMed  Google Scholar 

  113. 113

    Sherry, M. M., Reeves, A., Wu, J. K. & Cochran, B. H. STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 27, 2383–2392 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Kim, E. et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23, 839–852 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Smith, A. G. et al. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336, 688–690 (1988).

    CAS  Google Scholar 

  116. 116

    Murray, R., Lee, F. & Chiu, C. P. The genes for leukemia inhibitory factor and interleukin-6 are expressed in mouse blastocysts prior to the onset of hemopoiesis. Mol. Cell. Biol. 10, 4953–4956 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Pitman, M. et al. LIF receptor signaling modulates neural stem cell renewal. Mol. Cell. Neurosci. 27, 255–266 (2004).

    CAS  PubMed  Google Scholar 

  118. 118

    Guryanova, O. A. et al. Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3. Cancer Cell 19, 498–511 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Wang, H. et al. Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem Cells 27, 2393–2404 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Kroon, P. et al. JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells. Cancer Res. 73, 5288–5298 (2013).

    CAS  PubMed  Google Scholar 

  121. 121

    Rattigan, Y., Hsu, J.-M., Mishra, P. J., Glod, J. & Banerjee, D. Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu. Exp. Cell Res. 316, 3417–3424 (2010).

    CAS  PubMed  Google Scholar 

  122. 122

    Hsu, H. S. et al. Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway. Lung Cancer 75, 167–177 (2012).

    PubMed  Google Scholar 

  123. 123

    Krause, D. S. et al. Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nature Med. 19, 1513–1517 (2013).

    CAS  PubMed  Google Scholar 

  124. 124

    Jinushi, M. et al. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc. Natl Acad. Sci. USA 108, 12425–12430 (2011).

    CAS  PubMed  Google Scholar 

  125. 125

    Zhou, B. et al. Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal. J. Clin. Invest. 124, 553–563 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Chen, X. et al. Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells. J. Clin. Invest. 123, 2576–2589 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Su, Y. J., Lai, H. M., Chang, Y. W., Chen, G. Y. & Lee, J. L. Direct reprogramming of stem cell properties in colon cancer cells by CD44. EMBO J. 30, 3186–3199 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    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 (2012).

    CAS  PubMed  Google Scholar 

  129. 129

    Yuan, Z. L., Guan, Y. J., Chatterjee, D. & Chin, Y. E. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307, 269–273 (2005).

    CAS  PubMed  Google Scholar 

  130. 130

    Timofeeva, O. A. et al. Mechanisms of unphosphorylated STAT3 transcription factor binding to DNA. J. Biol. Chem. 287, 14192–14200 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Wu, J. et al. Kaposi's sarcoma-associated herpesvirus (KSHV) vIL-6 promotes cell proliferation and migration by upregulating DNMT1 via STAT3 activation. PLoS ONE 9, e93478 (2014).

    PubMed  PubMed Central  Google Scholar 

  132. 132

    Ambrogio, C. et al. NPM-ALK oncogenic tyrosine kinase controls T-cell identity by transcriptional regulation and epigenetic silencing in lymphoma cells. Cancer Res. 69, 8611–8619 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    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 (2013).

    PubMed  Google Scholar 

  134. 134

    Minami, J. et al. Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. Leukemia 28, 680–689 (2014).

    CAS  Google Scholar 

  135. 135

    Dawson, M. A. et al. JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin. Nature 461, 819–822 (2009). This report provides the first example of JAK2 regulating the cancer transcriptome.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Griffiths, D. S. et al. LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease. Nature Cell Biol. 13, 13–21 (2011).

    CAS  PubMed  Google Scholar 

  137. 137

    Wegrzyn, J. et al. Function of mitochondrial Stat3 in cellular respiration. Science 323, 793–797 (2009). This report, together with reference 139, is the first to describe an unexpected role of STAT3 in mitochondria.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Meier, J. A. & Larner, A. C. Toward a new STATe: the role of STATs in mitochondrial function. Semin. Immunol. 26, 20–28 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Gough, D. J. et al. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324, 1713–1716 (2009). This paper, together with reference 137, is the first to provide direct evidence for an important role of mitochondrial STAT3 in transformation.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Zhang, Q. et al. Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727. J. Biol. Chem. 288, 31280–31288 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Mackenzie, G. G. et al. Targeting mitochondrial STAT3 with the novel phospho-valproic acid (MDC-1112) inhibits pancreatic cancer growth in mice. PLoS ONE 8, e61532 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Mantel, C. et al. Mouse hematopoietic cell-targeted STAT3 deletion: stem/progenitor cell defects, mitochondrial dysfunction, ROS overproduction, and a rapid aging-like phenotype. Blood 120, 2589–2599 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Du, W. et al. Inhibition of JAK2/STAT3 signalling induces colorectal cancer cell apoptosis via mitochondrial pathway. J. Cell. Mol. Med. 16, 1878–1888 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Kortylewski, M. et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nature Biotech. 27, 925–932 (2009).

    CAS  Google Scholar 

  145. 145

    Zhang, Q. et al. TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo. Blood 121, 1304–1315 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Peterson, L. W. & Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nature Rev. Immunol. 14, 141–153 (2014).

    CAS  Google Scholar 

  147. 147

    Atreya, R. et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nature Med. 6, 583–588 (2000).

    CAS  PubMed  Google Scholar 

  148. 148

    Hruz, P., Dann, S. M. & Eckmann, L. STAT3 and its activators in intestinal defense and mucosal homeostasis. Curr. Opin. Gastroenterol. 26, 109–115 (2010).

    CAS  PubMed  Google Scholar 

  149. 149

    Ritter, S. L. & Hall, R. A. Fine-tuning of GPCR activity by receptor-interacting proteins. Nature Rev. Mol. Cell. Biol. 10, 819–830 (2009).

    CAS  Google Scholar 

  150. 150

    Rakoff-Nahoum, S. & Medzhitov, R. Toll-like receptors and cancer. Nature Rev. Cancer 9, 57–63 (2009).

    CAS  Google Scholar 

  151. 151

    Ferrand, A. et al. A novel mechanism for JAK2 activation by a G protein-coupled receptor, the CCK2R: implication of this signaling pathway in pancreatic tumor models. J. Biol. Chem. 280, 10710–10715 (2005).

    CAS  PubMed  Google Scholar 

  152. 152

    Calon, A. et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Gupta, M. et al. Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation. Blood 119, 2844–2853 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Marzec, M. et al. Differential effects of interleukin-2 and interleukin-15 versus interleukin-21 on CD4+ cutaneous T-cell lymphoma cells. Cancer Res. 68, 1083–1091 (2008).

    CAS  PubMed  Google Scholar 

  155. 155

    Wu, H. et al. MiR-135a targets JAK2 and inhibits gastric cancer cell proliferation. Cancer Biol. Ther. 13, 281–288 (2012).

    CAS  PubMed  Google Scholar 

  156. 156

    Hatziapostolou, M. et al. An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 147, 1233–1247 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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The authors thank many laboratories and members of their own groups that have made important discoveries on the topics of JAK/STAT pathways in cancer. Special thanks also go to those individuals whose publications are relevant to the topics in this Review but which were not cited owing to space limitations.

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Corresponding authors

Correspondence to Hua Yu or Heehyoung Lee or Richard Jove.

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The authors declare no competing financial interests.

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Immune checkpoint

A pathway or molecule that is capable of inhibiting immune responses. In normal physiology, immune checkpoints are crucial for maintenance of self-tolerance to minimize unwanted collateral tissue damage. However, they also act as brakes for desired antitumour immune responses when subverted by tumours.

Toll-like receptors

(TLRs). TLRs consist of multiple family members that have an important role in the innate immune system responses and are usually expressed in immune cells such as macrophages and dendritic cells. TLRs recognize many molecules that are associated with pathogens, such as bacterial cell-surface lipopolysaccharides, double-stranded RNA of viruses, and the unmethylated CpG islands of bacterial and viral DNA.


(miRNAs). Short non-coding RNAs with the ability to regulate gene expression at transcriptional and post-transcriptional levels. miRNA can silence genes owing to its capacity to base-pair with complementary sequences within mRNA strands, thereby preventing translation of the mRNA into protein.

G-protein-coupled receptors

(GPCRs). Membrane proteins with a broad range of functions in biological species throughout evolution. They are regulated by binding to the nucleotides GTP and GDP. Stimulation by external signalling molecules activates GPCRs via exchange of GDP for GTP, leading to their interaction with associated G subunit proteins that propagate intracellular signals.

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Yu, H., Lee, H., Herrmann, A. et al. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14, 736–746 (2014).

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