Role of STAT3 in Colorectal Cancer Development

  • Vajravathi Lakkim
  • Madhava C. Reddy
  • Durbaka V. R. Prasad
  • Dakshayani Lomada
Chapter

Abstract

Colorectal cancer is the cancer of the colon, located at the lower part of the digestive system. Although the role of STAT3 in cancer is known, its role particularly in colon cancer is largely unknown. STAT3 is a cytoplasmic transcription factor that involves extracellular signaling to the nucleus regulating fundamental functions, like cell proliferation, apoptosis, differentiation, and angiogenesis. STAT3 is a key regulator; abrogated activation leads to several diseases, including cancer. Aberrant interleukin (IL)-6-mediated JAK/STAT3 signaling pathway is closely related to the advancement of several human solid tumors including colorectal cancer. With other upstream regulators, IL-6/JAK signaling can activate STAT3, and its role appears to be critical in various types of cancer. STAT3 has been traditionally recognized as an oncogene; more recently the dual role of STAT3 in cancer, either tumor inductive or suppressive, has been appreciated. This chapter describes the potential role of STAT3 in colon cancer based on in vitro, in vivo, and patient studies. Furthermore, we will discuss the mechanism of action and roles of the IL-6/JAK/STAT3 pathway in colorectal cancer and exploit current therapeutic strategies, to treat colorectal cancer. Understanding the complexity of STAT3 function in colorectal cancer has the potential to elucidate important molecular aspects of colorectal cancer with significant therapeutic implications.

Keywords

Colorectal cancer STAT3 IL-6 JAKs Proliferation Migration Angiogenesis Therapeutics 

References

  1. 1.
    Agarwal C, Tyagi A et al (2007) Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells. Carcinogenesis 28(7):1463–1470PubMedCrossRefGoogle Scholar
  2. 2.
    Akira S, Nishio Y et al (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77(1):63–71PubMedCrossRefGoogle Scholar
  3. 3.
    Alas S, Bonavida B (2001) Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin’s lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res 61(13):5137–5144PubMedGoogle Scholar
  4. 4.
    Alix-Panabieres C, Schwarzenbach H et al (2012) Circulating tumor cells and circulating tumor DNA. Annu Rev Med 63:199–215PubMedCrossRefGoogle Scholar
  5. 5.
    Andersen JN, Mortensen OH et al (2001) Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol Cell Biol 21(21):7117–7136PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Arora T, Liu B et al (2003) PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4. J Biol Chem 278(24):21327–21330PubMedCrossRefGoogle Scholar
  7. 7.
    Atreya R, Mudter J et al (2000) 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. Nat Med 6(5):583–588PubMedCrossRefGoogle Scholar
  8. 8.
    Azare J, Leslie K et al (2007) Constitutively activated Stat3 induces tumorigenesis and enhances cell motility of prostate epithelial cells through integrin beta 6. Mol Cell Biol 27(12):4444–4453PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Barre B, Vigneron A et al (2005) The STAT3 transcription factor is a target for the Myc and riboblastoma proteins on the Cdc25A promoter. J Biol Chem 280(16):15673–15681PubMedCrossRefGoogle Scholar
  10. 10.
    Bartoli M, Platt D et al (2003) VEGF differentially activates STAT3 in microvascular endothelial cells. FASEB J17(11):1562–1564CrossRefGoogle Scholar
  11. 11.
    Beales IL, Garcia-Morales C et al (2014) Adiponectin inhibits leptin-induced oncogenic signalling in oesophageal cancer cells by activation of PTP1B. Mol Cell Endocrinol 382(1):150–158PubMedCrossRefGoogle Scholar
  12. 12.
    Bollrath J, Phesse TJ et al (2009) gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15(2):91–102PubMedCrossRefGoogle Scholar
  13. 13.
    Bosch-Barrera J, Menendez JA (2015) Silibinin and STAT3: a natural way of targeting transcription factors for cancer therapy. Cancer Treat Rev 41(6):540–546PubMedCrossRefGoogle Scholar
  14. 14.
    Bromberg J, Darnell JE Jr (2000) The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19(21):2468–2473PubMedCrossRefGoogle Scholar
  15. 15.
    Bromberg JF, Wrzeszczynska MH et al (1999) Stat3 as an oncogene. Cell 98(3):295–303PubMedCrossRefGoogle Scholar
  16. 16.
    Brown ME, Bear MD et al (2015) Characterization of STAT3 expression, signaling and inhibition in feline oral squamous cell carcinoma. BMC Vet Res 11:206PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Buettner R, Mora LB et al (2002) Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 8(4):945–954PubMedGoogle Scholar
  18. 18.
    Bünger S, Haug U et al (2012) A novel multiplex-protein array for serum diagnostics of colon cancer: a case–control study. BMC Cancer 12(1):1–12CrossRefGoogle Scholar
  19. 19.
    Cao W, Liu Y, Zhang R, Zhang B, Wang T, Zhu X, Mei L, Chen H, Zhang H, Ming P, Huang L (2015) Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells. Sci Rep 5(1):8477.  https://doi.org/10.1038/srep08477
  20. 20.
    Catlett-Falcone R, Landowski TH et al (1999) Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10(1):105–115PubMedCrossRefGoogle Scholar
  21. 21.
    Chen W, Daines MO et al (2004) Turning off signal transducer and activator of transcription (STAT): the negative regulation of STAT signaling. J Allergy Clin Immunol 114(3):476–489. quiz 490PubMedCrossRefGoogle Scholar
  22. 22.
    Chen Z, Han ZC (2008) STAT3: a critical transcription activator in angiogenesis. Med Res Rev 28(2):185–200PubMedCrossRefGoogle Scholar
  23. 23.
    Chung CD, Liao J et al (1997) Specific inhibition of Stat3 signal transduction by PIAS3. Science 278(5344):1803–1805PubMedCrossRefGoogle Scholar
  24. 24.
    Cinamon G, Matloubian M et al (2004) Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nat Immunol 5(7):713–720PubMedCrossRefGoogle Scholar
  25. 25.
    Coppola D, Parikh V et al (2009) Substantially reduced expression of PIAS1 is associated with colon cancer development. J Cancer Res Clin Oncol 135(9):1287–1291PubMedCrossRefGoogle Scholar
  26. 26.
    Corte H, Manceau G et al (2012) MicroRNA and colorectal cancer. Dig Liver Dis 44(3):195–200PubMedCrossRefGoogle Scholar
  27. 27.
    Croker BA, Kiu H et al (2008) SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol 19(4):414–422PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    da Silva Filho BF, Gurgel AP et al (2013) Circulating cell-free DNA in serum as a biomarker of colorectal cancer. J Clin Pathol 66(9):775–778PubMedCrossRefGoogle Scholar
  29. 29.
    Dabir S, Kluge A et al (2014) Low PIAS3 expression in malignant mesothelioma is associated with increased STAT3 activation and poor patient survival. Clin Cancer Res 20(19):5124–5132PubMedCrossRefGoogle Scholar
  30. 30.
    Dang CV (1999) c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 19(1):1–11PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Darnell JE Jr (1997) STATs and gene regulation. Science 277(5332):1630–1635PubMedCrossRefGoogle Scholar
  32. 32.
    Debidda M, Wang L et al (2005) A role of STAT3 in Rho GTPase-regulated cell migration and proliferation. J Biol Chem 280(17):17275–17285PubMedCrossRefGoogle Scholar
  33. 33.
    Deng N, Goh LK et al (2012) A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61(5):673–684PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Deng X, Zhao Y et al (2015) miR-519d-mediated downregulation of STAT3 suppresses breast cancer progression. Oncol Rep 34(4):2188–2194PubMedCrossRefGoogle Scholar
  35. 35.
    Diao J, Yang X et al (2015) Exosomal Hsp70 mediates immunosuppressive activity of the myeloid-derived suppressor cells via phosphorylation of Stat3. Med Oncol 32(2):453PubMedCrossRefGoogle Scholar
  36. 36.
    Diao Y, Wang X et al (2009) SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by inhibiting the leukemia inhibitory factor-induced JAK1/STAT1/STAT3 pathway. Mol Cell Biol 29(18):5084–5093PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Endo TA, Masuhara M et al (1997) A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387(6636):921–924PubMedCrossRefGoogle Scholar
  38. 38.
    Ernst M, Najdovska M et al (2008) STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest 118(5):1727–1738PubMedPubMedCentralGoogle Scholar
  39. 39.
    Fan MQ, Huang CB et al (2013a) Decrease expression of microRNA-20a promotes cancer cell proliferation and predicts poor survival of hepatocellular carcinoma. J Exp Clin Cancer Res 32(1):21PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Fan Y, Mao R et al (2013b) NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 4(3):176–185PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Fang S, Liu B et al (2014) Platelet factor 4 inhibits IL-17/Stat3 pathway via upregulation of SOCS3 expression in melanoma. Inflammation 37(5):1744–1750PubMedCrossRefGoogle Scholar
  42. 42.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767PubMedCrossRefGoogle Scholar
  43. 43.
    Fenton JI, Birmingham JM (2010) Adipokine regulation of colon cancer: adiponectin attenuates interleukin-6-induced colon carcinoma cell proliferation via STAT-3. Mol Carcinog 49(7):700–709PubMedPubMedCentralGoogle Scholar
  44. 44.
    Frank DA (2007) STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett 251(2):199–210PubMedCrossRefGoogle Scholar
  45. 45.
    Fujisaki K, Fujimoto H et al (2015) Cancer-mediated adipose reversion promotes cancer cell migration via IL-6 and MCP-1. Breast Cancer Res Treat 150(2):255–263PubMedCrossRefGoogle Scholar
  46. 46.
    Fujiwara Y, Takeya M et al (2014) A novel strategy for inducing the antitumor effects of triterpenoid compounds: blocking the protumoral functions of tumor-associated macrophages via STAT3 inhibition. Biomed Res Int 2014:348539PubMedPubMedCentralGoogle Scholar
  47. 47.
    Galaktionov K, Chen X et al (1996) Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 382(6591):511–517PubMedCrossRefGoogle Scholar
  48. 48.
    Galon J, Costes A et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964PubMedCrossRefGoogle Scholar
  49. 49.
    Garcia R, Bowman TL et al (2001) Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20(20):2499–2513PubMedCrossRefGoogle Scholar
  50. 50.
    Gassmann P, Haier J (2008) The tumor cell-host organ interface in the early onset of metastatic organ colonisation. Clin Exp Metastasis 25(2):171–181PubMedCrossRefGoogle Scholar
  51. 51.
    George J, Lim JS et al (2015) Comprehensive genomic profiles of small cell lung cancer. Nature 524(7563):47–53PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Grandis JR, Drenning SD et al (1998) Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth in vitro. J Clin Invest 102(7):1385–1392PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Grivennikov S, Karin E et al (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15(2):103–113PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Grivennikov SI (2013) IL-11: a prominent pro-tumorigenic member of the IL-6 family. Cancer Cell 24(2):145–147PubMedCrossRefGoogle Scholar
  55. 55.
    Grivennikov SI, Greten FR et al (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Grivennikov SI, Wang K et al (2012) Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491(7423):254–258PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Groot Koerkamp B, Rahbari NN et al (2013) Circulating tumor cells and prognosis of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer: a meta-analysis. Ann Surg Oncol 20(7):2156–2165PubMedCrossRefGoogle Scholar
  58. 58.
    Grunstein J, Roberts WG et al (1999) Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res 59(7):1592–1598PubMedGoogle Scholar
  59. 59.
    Gupta SC, Phromnoi K et al (2013) Morin inhibits STAT3 tyrosine 705 phosphorylation in tumor cells through activation of protein tyrosine phosphatase SHP1. Biochem Pharmacol 85(7):898–912PubMedCrossRefGoogle Scholar
  60. 60.
    Herrmann A, Priceman SJ et al (2014) CTLA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cells. J Clin Invest 124(7):2977–2987PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Herszenyi L, Farinati F et al (2008) Chemoprevention of colorectal cancer: feasibility in everyday practice? Eur J Cancer Prev 17(6):502–514PubMedCrossRefGoogle Scholar
  62. 62.
    Hoekstra E, Peppelenbosch MP et al (2012) The role of protein tyrosine phosphatases in colorectal cancer. Biochim Biophys Acta 1826(1):179–188PubMedGoogle Scholar
  63. 63.
    Hruz P, Dann SM et al (2010) STAT3 and its activators in intestinal defense and mucosal homeostasis. Curr Opin Gastroenterol 26(2):109–115PubMedCrossRefGoogle Scholar
  64. 64.
    Hwang JH, Kim DW et al (2003) Activation of signal transducer and activator of transcription 3 by oncogenic RET/PTC (rearranged in transformation/papillary thyroid carcinoma) tyrosine kinase: roles in specific gene regulation and cellular transformation. Mol Endocrinol 17(6):1155–1166PubMedCrossRefGoogle Scholar
  65. 65.
    Iliopoulos D, Hirsch HA et al (2009) An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139(4):693–706PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Irie-Sasaki J, Sasaki T et al (2001) CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409(6818):349–354PubMedCrossRefGoogle Scholar
  67. 67.
    Jain N, Zhang T et al (1999) Protein kinase C delta associates with and phosphorylates Stat3 in an interleukin-6-dependent manner. J Biol Chem 274(34):24392–24400PubMedCrossRefGoogle Scholar
  68. 68.
    Jarnicki A, Putoczki T et al (2010) Stat3: linking inflammation to epithelial cancer – more than a “gut” feeling? Cell Div 5(1):1–15CrossRefGoogle Scholar
  69. 69.
    Jenkins BJ, Grail D et al (2005) Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nat Med 11(8):845–852PubMedCrossRefGoogle Scholar
  70. 70.
    Kamath S, Buolamwini JK (2006) Targeting EGFR and HER-2 receptor tyrosine kinases for cancer drug discovery and development. Med Res Rev 26(5):569–594PubMedCrossRefGoogle Scholar
  71. 71.
    Kinnebrew MA, Pamer EG (2012) Innate immune signaling in defense against intestinal microbes. Immunol Rev 245(1):113–131PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Kojima H, Sasaki T et al (2005) STAT3 regulates nemo-like kinase by mediating its interaction with IL-6-stimulated TGF beta-activated kinase 1 for STAT3 Ser-727 phosphorylation. Proc Natl Acad Sci U S A A102(12):4524–4529CrossRefGoogle Scholar
  73. 73.
    Kong W, He L et al (2014) Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer. Oncogene 33(6):679–689PubMedCrossRefGoogle Scholar
  74. 74.
    Kortylewski M, Xin H et al (2009) Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell 15(2):114–123PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Lee H, Zhang P et al (2012) Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation. Proc Natl Acad Sci U S A A109(20):7765–7769CrossRefGoogle Scholar
  76. 76.
    Leslie K, Lang C et al (2006) Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res 66(5):2544–2552PubMedCrossRefGoogle Scholar
  77. 77.
    Levy DE (1999) Physiological significance of STAT proteins: investigations through gene disruption in vivo. Cell Mol Life Sci 55(12):1559–1567PubMedCrossRefGoogle Scholar
  78. 78.
    Levy DE, Lee CK (2002) What does Stat3 do? J Clin Invest 109(9):1143–1148PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Lim WA, Pawson T (2010) Phosphotyrosine signaling: evolving a new cellular communication system. Cell 142(5):661–667PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Liu BS, Cao Y et al (2014) TLR-mediated STAT3 and ERK activation controls IL-10 secretion by human B cells. Eur J Immunol 44(7):2121–2129PubMedCrossRefGoogle Scholar
  81. 81.
    Matsuura A, Lee HH (2013) Crystal structure of GTPase-activating domain from human MgcRacGAP. Biochem Biophys Res Commun 435(3):367–372PubMedCrossRefGoogle Scholar
  82. 82.
    McCarty OJ, Mousa SA et al (2000) Immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions. Blood 96(5):1789–1797PubMedGoogle Scholar
  83. 83.
    Miranda C, Fumagalli T et al (2010) Role of STAT3 in in vitro transformation triggered by TRK oncogenes. PLoS One 5(3):e9446PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Misale S, Yaeger R et al (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486(7404):532–536PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Morikawa T, Baba Y et al (2011) STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers. Clin Cancer Res 17(6):1452–1462PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Neel BG, Tonks NK (1997) Protein tyrosine phosphatases in signal transduction. Curr Opin Cell Biol 9(2):193–204PubMedCrossRefGoogle Scholar
  87. 87.
    Nguyen DX, Bos PD et al (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9(4):274–284PubMedCrossRefGoogle Scholar
  88. 88.
    Nicholson SE, Willson TA et al (1999) Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J18(2):375–385CrossRefGoogle Scholar
  89. 89.
    Niu G, Wright KL et al (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21(13):2000–2008PubMedCrossRefGoogle Scholar
  90. 90.
    Niu G, Wright KL et al (2005) Role of Stat3 in regulating p53 expression and function. Mol Cell Biol 25(17):7432–7440PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    O’Dwyer D, Ralton LD et al (2011) The proteomics of colorectal cancer: identification of a protein signature associated with prognosis. PLoS One 6(11):e27718PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Ochi A, Nguyen AH et al (2012) MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med 209(9):1671–1687PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Ohbayashi N, Ikeda O et al (2007) LIF- and IL-6-induced acetylation of STAT3 at Lys-685 through PI3K/Akt activation. Biol Pharm Bull 30(10):1860–1864PubMedCrossRefGoogle Scholar
  94. 94.
    Olayioye MA, Beuvink I et al (1999) ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases. J Biol Chem 274(24):17209–17218PubMedCrossRefGoogle Scholar
  95. 95.
    Patel K, Kollory A et al (2014) MicroRNA let-7 downregulates STAT3 phosphorylation in pancreatic cancer cells by increasing SOCS3 expression. Cancer Lett 347(1):54–64PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Peddareddigari VG, Wang D et al (2010) The tumor microenvironment in colorectal carcinogenesis. Cancer Microenviron 3(1):149–166PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Penuelas S, Anido J et al (2009) TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15(4):315–327PubMedCrossRefGoogle Scholar
  98. 98.
    Peterson LW, Artis D (2014) Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 14(3):141–153PubMedCrossRefGoogle Scholar
  99. 99.
    Putoczki TL, Thiem S et al (2013) Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell 24(2):257–271PubMedCrossRefGoogle Scholar
  100. 100.
    Rakoff-Nahoum S, Medzhitov R (2007) Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317(5834):124–127PubMedCrossRefGoogle Scholar
  101. 101.
    Raptis L, Arulanandam R et al (2011) The R(h)oads to Stat3: Stat3 activation by the Rho GTPases. Exp Cell Res 317(13):1787–1795PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Ray RM, Bhattacharya S et al (2005) Protein phosphatase 2A regulates apoptosis in intestinal epithelial cells. J Biol Chem 280(35):31091–31100PubMedCrossRefGoogle Scholar
  103. 103.
    Reddy KR, Guan Y et al (2011) Combined treatment targeting HIF-1alpha and Stat3 is a potent strategy for prostate cancer therapy. Prostate 71(16):1796–1809PubMedCrossRefGoogle Scholar
  104. 104.
    Remy I, Wilson IA et al (1999) Erythropoietin receptor activation by a ligand-induced conformation change. Science 283(5404):990–993PubMedCrossRefGoogle Scholar
  105. 105.
    Rosen H, Goetzl EJ (2005) Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 5(7):560–570PubMedCrossRefGoogle Scholar
  106. 106.
    Salcedo R, Worschech A et al (2010) MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J Exp Med 207(8):1625–1636PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732PubMedCrossRefGoogle Scholar
  108. 108.
    Shi S, Larson K et al (2008) Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability. Nat Cell Biol 10(4):489–496PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Shimwell NJ, Wei W et al (2010) Assessment of novel combinations of biomarkers for the detection of colorectal cancer. Cancer Biomark 7(3):123–132PubMedCrossRefGoogle Scholar
  110. 110.
    Shirogane T, Fukada T et al (1999) Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 11(6):709–719PubMedCrossRefGoogle Scholar
  111. 111.
    Shuai K (2000) Modulation of STAT signaling by STAT-interacting proteins. Oncogene 19(21):2638–2644PubMedCrossRefGoogle Scholar
  112. 112.
    Shuai K, Liu B (2005) Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 5(8):593–605PubMedCrossRefGoogle Scholar
  113. 113.
    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67(1):7–30Google Scholar
  114. 114.
    Silver DL, Naora H et al (2004) Activated signal transducer and activator of transcription (STAT) 3: localization in focal adhesions and function in ovarian cancer cell motility. Cancer Res 64(10):3550–3558Google Scholar
  115. 115.
    Silver JS, Hunter CA (2010) gp130 at the nexus of inflammation, autoimmunity, and cancer. J Leukoc Biol 88(6):1145–1156PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Song L, Turkson J et al (2003) Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene 22(27):4150–4165PubMedCrossRefGoogle Scholar
  117. 117.
    Sriuranpong V, Park JI et al (2003) Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer Res 63(11):2948–2956PubMedGoogle Scholar
  118. 118.
    Stark GR, Darnell JE Jr (2012) The JAK-STAT pathway at twenty. Immunity 36(4):503–514PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Stoleriu MG, Steger V et al (2014) A new strategy in the treatment of chemoresistant lung adenocarcinoma via specific siRNA transfection of SRF, E2F1, survivin, HIF and STAT3. Eur J Cardiothorac Surg 46(5):877–886PubMedCrossRefGoogle Scholar
  120. 120.
    Suiqing C, Min Z et al (2005) Overexpression of phosphorylated-STAT3 correlated with the invasion and metastasis of cutaneous squamous cell carcinoma. J Dermatol 32(5):354–360PubMedCrossRefGoogle Scholar
  121. 121.
    Sun X, Sui Q et al (2013) Targeting blockage of STAT3 in hepatocellular carcinoma cells augments NK cell functions via reverse hepatocellular carcinoma-induced immune suppression. Mol Cancer Ther 12(12):2885–2896PubMedCrossRefGoogle Scholar
  122. 122.
    Szabo-Fresnais N, Lefebvre F et al (2010) A new regulation of IL-6 production in adult cardiomyocytes by beta-adrenergic and IL-1 beta receptors and induction of cellular hypertrophy by IL-6 trans-signalling. Cell Signal 22(7):1143–1152PubMedCrossRefGoogle Scholar
  123. 123.
    Tang YJ, Sun ZL et al (2015) Inhibitor of signal transducer and activator of transcription 3 (STAT3) suppresses ovarian cancer growth, migration and invasion and enhances the effect of cisplatin in vitro. Genet Mol Res 14(1):2450–2460PubMedCrossRefGoogle Scholar
  124. 124.
    Teng TS, Lin B et al (2009) Stat3 promotes directional cell migration by regulating Rac1 activity via its activator betaPIX. J Cell Sci 122(Pt 22):4150–4159PubMedCrossRefGoogle Scholar
  125. 125.
    Theiss AL (2013) Sphingosine-1-phosphate: driver of NFkappaB and STAT3 persistent activation in chronic intestinal inflammation and colitis-associated cancer. JAKSTAT 2(3):e24150PubMedPubMedCentralGoogle Scholar
  126. 126.
    Thomas CY, Chouinard M et al (2003) Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells. Int J Cancer 104(1):19–27PubMedCrossRefGoogle Scholar
  127. 127.
    Timofeeva OA, Chasovskikh S et al (2012) Mechanisms of unphosphorylated STAT3 transcription factor binding to DNA. J Biol Chem 287(17):14192–14200PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Timofeeva OA, Tarasova NI et al (2013) STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain. Proc Natl Acad Sci USA A110(4):1267–1272CrossRefGoogle Scholar
  129. 129.
    Toiyama Y, Takahashi M et al (2013) Serum miR-21 as a diagnostic and prognostic biomarker in colorectal cancer. J Natl Cancer Inst 105(12):849–859PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Tonozuka Y, Minoshima Y et al (2004) A GTPase-activating protein binds STAT3 and is required for IL-6-induced STAT3 activation and for differentiation of a leukemic cell line. Blood 104(12):3550–3557PubMedCrossRefGoogle Scholar
  131. 131.
    Tye H, Kennedy CL et al (2012) STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell 22(4):466–478PubMedCrossRefGoogle Scholar
  132. 132.
    Vicari AP, Caux C et al (2002) Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol 12(1):33–42PubMedCrossRefGoogle Scholar
  133. 133.
    Vigneron A, Gamelin E et al (2008) The EGFR-STAT3 oncogenic pathway up-regulates the Eme1 endonuclease to reduce DNA damage after topoisomerase I inhibition. Cancer Res 68(3):815–825PubMedCrossRefGoogle Scholar
  134. 134.
    Wang R, Cherukuri P et al (2005) Activation of Stat3 sequence-specific DNA binding and transcription by p300/CREB-binding protein-mediated acetylation. J Biol Chem 280(12):11528–11534PubMedCrossRefGoogle Scholar
  135. 135.
    Wang T, Niu G et al (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10(1):48–54PubMedCrossRefGoogle Scholar
  136. 136.
    Wang YX, Cai H et al (2014) Silibinin inhibits proliferation, induces apoptosis and causes cell cycle arrest in human gastric cancer MGC803 cells via STAT3 pathway inhibition. Asian Pac J Cancer Prev 15(16):6791–6798PubMedCrossRefGoogle Scholar
  137. 137.
    Weerasinghe P, Garcia GE et al (2007) Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. Int J Oncol 31(1):129–136PubMedGoogle Scholar
  138. 138.
    Wilson HM (2014) SOCS proteins in macrophage polarization and function. Front Immunol 5:357PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Wu L, Du H et al (2011) Signal transducer and activator of transcription 3 (Stat3C) promotes myeloid-derived suppressor cell expansion and immune suppression during lung tumorigenesis. Am J Pathol 179(4):2131–2141PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Xiao H, Bid HK et al (2015) A novel small molecular STAT3 inhibitor, LY5, inhibits cell viability, cell migration, and angiogenesis in medulloblastoma cells. J Biol Chem 290(6):3418–3429PubMedCrossRefGoogle Scholar
  141. 141.
    Xie TX, Wei D et al (2004) Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 23(20):3550–3560PubMedCrossRefGoogle Scholar
  142. 142.
    Xu H, Yu Y et al (2005a) Epidermal growth factor receptor (EGFR)-related protein inhibits multiple members of the EGFR family in colon and breast cancer cells. Mol Cancer Ther 4(3):435–442PubMedGoogle Scholar
  143. 143.
    Xu Q, Briggs J et al (2005b) Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 24(36):5552–5560PubMedCrossRefGoogle Scholar
  144. 144.
    Yahata Y, Shirakata Y et al (2003) Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. J Biol Chem 278(41):40026–40031PubMedCrossRefGoogle Scholar
  145. 145.
    Yang J, Liao X et al (2007) Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev 21(11):1396–1408PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Yang XJ, Seto E (2007) HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26(37):5310–5318PubMedCrossRefGoogle Scholar
  147. 147.
    Ying H, Da L et al (2013) TLR4 mediates MAPK-STAT3 axis activation in bladder epithelial cells. Inflammation 36(5):1064–1074PubMedCrossRefGoogle Scholar
  148. 148.
    Yu CL, Meyer DJ et al (1995) Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269(5220):81–83PubMedCrossRefGoogle Scholar
  149. 149.
    Yu CY, Wang L et al (2002) STAT3 activation is required for interleukin-6 induced transformation in tumor-promotion sensitive mouse skin epithelial cells. Oncogene 21(25):3949–3960PubMedCrossRefGoogle Scholar
  150. 150.
    Yu H, Lee H et al (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14(11):736–746PubMedCrossRefGoogle Scholar
  151. 151.
    Yuan ZL, Guan YJ et al (2005) Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307(5707):269–273PubMedCrossRefGoogle Scholar
  152. 152.
    Zaki MH, Vogel P et al (2010) IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J Immunol 185(8):4912–4920PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Zhuang G, Wu X et al (2012) Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J31(17):3513–3523CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  • Vajravathi Lakkim
    • 1
  • Madhava C. Reddy
    • 2
  • Durbaka V. R. Prasad
    • 3
  • Dakshayani Lomada
    • 1
  1. 1.Department of Genetics and GenomicsYogi Vemana UniversityKadapaIndia
  2. 2.Department of Biotechnology and BioinformaticsYogi Vemana UniversityKadapaIndia
  3. 3.Department of MicrobiologyYogi Vemana UniversityKadapaIndia

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