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Role of STAT3 in Gastric Cancer Initiation, Development, and Progression

  • Aleem Basha Pinjari
  • Abdul Razak Meerza
Chapter

Abstract

Gastric cancer (GC), a leading cancer that occupies the second position in terms of morbidity and mortality, occupies the fourth place of all cancers in terms of manifestation. Annual gastric cancer manifestations are reaching several millions of deaths along with millions of new cases. Gastric cancer which is not detected in the early stages has very poor prognosis, and the 5-year survival rate is only around 20%. Gastric cancer development includes numerous alterations at genome level leading to changes in the expression of quite a lot of genes involved in several physiological processes. Even though a number of factors showed their role in advancement of GC, a link between STAT3 and the risk of GC has become apparent in current years. Signal transducers and activators of transcriptions (STATs) which are predominantly known for their role as transcription factors are implicated in controlling numerous physiological processes such as cell propagation, differentiation, apoptosis, and angiogenesis by controlling the expression of critical genes in the pathway. Abnormal activation of STAT3 plays a key role in inflammation and transformation in numerous cancers including gastric cancer (GC). Earlier, STAT3 has never been considered as a target, and hence there is no FDA-approved STAT3 inhibitor till now. Recent advances in drug discovery and cancer biology now focused on STAT3 globally for treating different types of cancers. The present chapter summarizes the recent literature and gives an idea about involvement of STAT3 in gastric cancer initiation and progression.

Keywords

STAT3 Inflammation Signal transduction Gastric cancer 

Notes

Acknowledgment

The author gratefully acknowledges DST-SERB, Government of India, for the financial support in the form of DST-Young Scientist under the SERB File No. YSS/2015/000860.

References

  1. 1.
    Adams JC (2004) Roles of fascin in cell adhesion and motility. Curr Opin Cell Biol 16(5):590–596CrossRefPubMedGoogle Scholar
  2. 2.
    Akira S, Nishio Y, Inoue M, Wang XJ, We S, Matsusaka T, Kishimoto T (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):63–71CrossRefPubMedGoogle Scholar
  3. 3.
    Alberts SR, Cervantes A, Van de Velde CJH (2003) Gastric cancer: epidemiology, pathology and treatment. Ann Oncol 14(90002):31–36CrossRefGoogle Scholar
  4. 4.
    Alexandrow MG, Song LJ, Altiok S, Gray J, Haura EB, Kumar NB (2012) Curcumin: a novel stat 3 pathway inhibitor for chemoprevention of lung cancer. Eur J Cancer Prev 21(5):407CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Mustelin T (2004) Protein tyrosine phosphatases in the human genome. Cell 117(6):699–711CrossRefPubMedGoogle Scholar
  6. 6.
    Alvarez RH, Kantarjian HM, Cortes JE (2006) The role of Src in solid and hematologic malignancies. Cancer 107(8):1918–1929CrossRefPubMedGoogle Scholar
  7. 7.
    Amin HM, McDonnell TJ, Ma Y, Lin Q, Fujio Y, Kunisada K, Medeiros LJ (2004) Selective inhibition of STAT3 induces apoptosis and G1 cell cycle arrest in ALK-positive anaplastic large cell lymphoma. Oncogene 23(32):5426–5434CrossRefPubMedGoogle Scholar
  8. 8.
    Anglesio MS, George J, Kulbe H, Friedlander M, Rischin D, Lemech C, Chakravarty P (2011) IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clin Cancer Res 17(8):2538–2548CrossRefPubMedGoogle Scholar
  9. 9.
    Axon A (2006) Symptoms and diagnosis of gastric cancer at early curable stage. Best Pract Res Clin Gastroenterol 20(4):697–708CrossRefPubMedGoogle Scholar
  10. 10.
    Azare J, Leslie K, Al-Ahmadie H, Gerald W, Weinreb PH, Violette SM, Bromberg J (2007) Constitutively activated STAT3 induces tumorigenesis and enhances cell motility of prostate epithelial cells through integrin β6. Mol Cell Biol 27(12):4444–4453CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Aznar S, Valerón PF, del Rincon SV, Pérez LF, Perona R, Lacal JC (2001) Simultaneous tyrosine and serine phosphorylation of STAT3 transcription factor is involved in Rho A GTPase oncogenic transformation. Mol Biol Cell 12(10):3282–3294CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Barnhart BC, Legembre P, Pietras E, Bubici C, Franzoso G, Peter ME (2004) CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells. EMBO J 23(15):3175–3185CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Becker S, Groner B, Müller CW (1998) Three-dimensional structure of the Stat3β homodimer bound to DNA. Nature 394(6689):145–151CrossRefPubMedGoogle Scholar
  14. 14.
    Bromberg J (2002) Stat proteins and oncogenesis. J Clin Invest 109(9):1139–1142CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE (1999) STAT3 as an oncogene. Cell 98(3):295–303CrossRefPubMedGoogle Scholar
  16. 16.
    Bronte-Tinkew DM, Terebiznik M, Franco A, Ang M, Ahn D, Mimuro H, Jones NL (2009) Helicobacter pylori cytotoxin-associated gene A activates the signal transducer and activator of transcription 3 pathway in vitro and in vivo. Cancer Res 69(2):632–639CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Cabral MM, Mendes C, Castro LP, Cartelle CT, Guerra J, Queiroz DM, Nogueira AM (2006) Apoptosis in Helicobacter pylori gastritis is related to cagA status. Helicobacter 11(5):469–476CrossRefPubMedGoogle Scholar
  18. 18.
    Calvet X, Ramírez Lázaro MJ, Lehours P, Mégraud F (2013) Diagnosis and epidemiology of Helicobacter pylori infection. Helicobacter 18(s1):5–11CrossRefPubMedGoogle Scholar
  19. 19.
    Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Dalton WS (1999) Constitutive activation of STAT3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10(1):105–115CrossRefPubMedGoogle Scholar
  20. 20.
    Chan AOO, Luk JM, Hui WM, Lam SK (1999) Molecular biology of gastric carcinoma: from laboratory to bedside. J Gastroenterol Hepatol 14(12):1150–1160CrossRefPubMedGoogle Scholar
  21. 21.
    Chang TLY, Mosoian A, Pine R, Klotman ME, Moore JP (2002) A soluble factor (s) secreted from CD8+ T lymphocytes inhibits human immunodeficiency virus type 1 replication through STAT1 activation. J Virol 76(2):569–581CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Chen X, Vinkemeier U, Zhao Y, Jeruzalmi D, Darnell JE, Kuriyan J (1998) Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 93(5):827–839CrossRefPubMedGoogle Scholar
  23. 23.
    Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Sci-AAAS-Wkly Pap Ed-Incl Guid Sci Inf 264(5164):1415–1420Google Scholar
  24. 24.
    Deng X, Cao M, Zhang J, Hu K, Yin Z, Zhou Z, …, Zeng Y (2014) Hyaluronic acid-chitosan nanoparticles for co-delivery of MiR-34a and doxorubicin in therapy against triple negative breast cancer. Biomaterials 35(14):4333–4344CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Durães C, Almeida GM, Seruca R, Oliveira C, Carneiro F (2014) Biomarkers for gastric cancer: prognostic, predictive or targets of therapy? Virchows Arch 464(3):367–378CrossRefPubMedGoogle Scholar
  26. 26.
    Durbin JE, Hackenmiller R, Simon MC, Levy DE (1996) Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84(3):443–450CrossRefPubMedGoogle Scholar
  27. 27.
    Frame MC (2002) Src in cancer: deregulation and consequences for cell behaviour. Biochim Biophys Acta (BBA)-Rev Cancer 1602(2):114–130CrossRefGoogle Scholar
  28. 28.
    Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Hirano T (1996) Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5(5):449–460CrossRefPubMedGoogle Scholar
  29. 29.
    Giraud S, Bienvenu F, Avril S, Gascan H, Heery DM, Coqueret O (2002) Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a. J Biol Chem 277(10):8004–8011CrossRefPubMedGoogle Scholar
  30. 30.
    Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS, Gallick GE (2005) HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene 24(19):3110–3120CrossRefPubMedGoogle Scholar
  31. 31.
    Guo C, Yang G, Khun K, Kong X, Levy D, Lee P, Melamed J (2009) Activation of STAT3 in renal tumors. Am J Transl Res 1(3):283–290PubMedPubMedCentralGoogle Scholar
  32. 32.
    Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334(2):297–314CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hirano T, Ishihara K, Hibi M (2000) Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19(21):2548–2556CrossRefPubMedGoogle Scholar
  34. 34.
    Huang Y, Yang M, Yang H, Zeng Z (2010) Upregulation of the GRIM-19 gene suppresses invasion and metastasis of human gastric cancer SGC-7901 cell line. Exp Cell Res 316(13):2061–2070CrossRefPubMedGoogle Scholar
  35. 35.
    Improta T, Pine R (1997) Susceptibility to virus infection is determined by a Stat-mediated response to the autocrine effect of virus-induced type I interferon. Cytokine 9(6):383–393CrossRefPubMedGoogle Scholar
  36. 36.
    Jackson CB, Judd LM, Menheniott TR, Kronborg I, Dow C, Yeomans ND, Giraud AS (2007) Augmented gp130-mediated cytokine signalling accompanies human gastric cancer progression. J Pathol 213(2):140–151CrossRefPubMedGoogle Scholar
  37. 37.
    Judd LM, Bredin K, Kalantzis A, Jenkins BJ, Ernst M, Giraud AS (2006) STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis. Gastroenterology 131(4):1073–1085CrossRefPubMedGoogle Scholar
  38. 38.
    Kanda N, Seno H, Konda Y, Marusawa H, Kanai M, Nakajima T, Sekikawa A (2004) STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene 23(28):4921–4929CrossRefPubMedGoogle Scholar
  39. 39.
    Kaplan MH, Grusby MJ (1998) Regulation of T helper cell differentiation by STAT molecules. J Leukoc Biol 64(1):2–5CrossRefPubMedGoogle Scholar
  40. 40.
    Kaplan MH, Sun YL, Hoey T, Grusby MJ (1996) Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382(6587):174CrossRefPubMedGoogle Scholar
  41. 41.
    Kuo CT, Leiden JM (1999) Transcriptional regulation of T lymphocyte development and function. Annu Rev Immunol 17(1):149–187CrossRefPubMedGoogle Scholar
  42. 42.
    Lai SY, Johnson FM (2010) Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches. Drug Resist Updat 13(3):67–78CrossRefPubMedGoogle Scholar
  43. 43.
    Lee JH, Kaminski N, Dolganov G, Grunig G, Koth L, Solomon C, …, Sheppard D (2001) Interleukin-13 induces dramatically different transcriptional programs in three human airway cell types. Am J Respir Cell Mol Biol 25(4):474–485CrossRefPubMedGoogle Scholar
  44. 44.
    Levy DE, Darnell JE (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3(9):651–662CrossRefPubMedGoogle Scholar
  45. 45.
    Li M, Liu W, Zhu YF, Chen YL, Zhang BZ, Wang R (2006) Correlation of COX-2 and K-ras expression to clinical outcome in gastric cancer. Acta Oncol 45(8):1115–1119CrossRefPubMedGoogle Scholar
  46. 46.
    Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y, …, Hung MC (2007) Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res 67(19):9066–9076CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Macha MA, Matta A, Kaur J, Chauhan SS, Thakar A, Shukla NK, Ralhan R (2011) Prognostic significance of nuclear pSTAT3 in oral cancer. Head Neck 33(4):482–489CrossRefPubMedGoogle Scholar
  48. 48.
    Machesky LM, Li A (2010) Fascin: invasive filopodia promoting metastasis. Commun Integr Biol 3(3):263–270CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Mali SB (2015) Review of STAT3 (Signal Transducers and Activators of Transcription) in head and neck cancer. Oral Oncol 51(6):565–569CrossRefPubMedGoogle Scholar
  50. 50.
    Mao X, Ren Z, Parker GN, Sondermann H, Pastorello MA, Wang W, Chen X (2005) Structural bases of unphosphorylated STAT1 association and receptor binding. Mol Cell 17(6):761–771CrossRefPubMedGoogle Scholar
  51. 51.
    Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T, Yokota T (1999) STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO J 18(15):4261–4269CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Mohrs M, Lacy DA, Locksley RM (2003) Stat signals release activated naive Th cells from an anergic checkpoint. J Immunol 170(4):1870–1876CrossRefPubMedGoogle Scholar
  53. 53.
    Mora LB, Buettner R, Seigne J, Diaz J, Ahmad N, Garcia R, Muro-Cacho C (2002) Constitutive activation of STAT3 in human prostate tumors and cell lines direct inhibition of STAT3 signaling induces apoptosis of prostate cancer cells. Cancer Res 62(22):6659–6666PubMedGoogle Scholar
  54. 54.
    Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, Wang D, …, Grosveld GC (1999) Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10(2):249–259CrossRefPubMedGoogle Scholar
  55. 55.
    Murray PJ (2007) The JAK-STAT signaling pathway: input and output integration. J Immunol 178(5):2623–2629CrossRefPubMedGoogle Scholar
  56. 56.
    Ning ZQ, Li J, McGuinness M, Arceci RJ (2001) STAT3 activation is required for Asp816 mutant c-Kit induced tumorigenicity. Oncogene 20(33):4528CrossRefPubMedGoogle Scholar
  57. 57.
    Owen-Schaub LB, Meterissian S, Ford RJ (1993) Fas/APO-1 expression and function on malignant cells of hematologic and nonhematologic origin. J Immunother 14(3):234–241CrossRefGoogle Scholar
  58. 58.
    Pan H, Hong F, Radaeva S, Gao B (2004) Hydrodynamic gene delivery of interleukin-22 protects the mouse liver from concanavalin A-, carbon tetrachloride-, and Fas ligand-induced injury via activation of STAT3. Cell Mol Immunol 1(1):43–49PubMedGoogle Scholar
  59. 59.
    Schindler C, Plumlee C (2008) Interferons pen the JAK–STAT pathway. In: Seminars in cell & developmental biology, vol. 19, no. 4. Academic Press, Cambridge, MA, pp 311–318CrossRefGoogle Scholar
  60. 60.
    Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282(28):20059–20063CrossRefPubMedGoogle Scholar
  61. 61.
    Seidel HM, Milocco LH, Lamb P, Darnell JE, Stein RB, Rosen J (1995) Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity. Proc Natl Acad Sci 92(7):3041–3045CrossRefPubMedGoogle Scholar
  62. 62.
    Shah NG, Trivedi TI, Tankshali RA, Goswami JV, Jetly DH, Shukla SN, Verma RJ (2009) Prognostic significance of molecular markers in oral squamous cell carcinoma: a multivariate analysis. Head Neck 31(12):1544–1556CrossRefPubMedGoogle Scholar
  63. 63.
    Shaulian E (2010) AP-1 – the Jun proteins: oncogenes or tumor suppressors in disguise? Cell Signal 22(6):894–899CrossRefPubMedGoogle Scholar
  64. 64.
    Sheen-Chen SM, Huang CC, Tang RP, Chou FF, Eng HL (2008) Prognostic value of signal transducers and activators of transcription 3 in breast cancer. Cancer Epidemiol Biomark Prev 17(9):2286–2290CrossRefGoogle Scholar
  65. 65.
    Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Chu C, Quelle FW, Nosaka T, Vignali DA, Doherty PC, Grosveld G, Paul WE, Ihle JN (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380:630–633CrossRefPubMedGoogle Scholar
  66. 66.
    Shinohara H, Yagita H, Ikawa Y, Oyaizu N (2000) Fas drives cell cycle progression in glioma cells via extracellular signal-regulated kinase activation. Cancer Res 60(6):1766–1772PubMedGoogle Scholar
  67. 67.
    Siewert JR, Böttcher K, Stein HJ, Roder JD (1998) Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg 228(4):449CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Silva CM (2004) Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 23(48):8017–8023CrossRefPubMedGoogle Scholar
  69. 69.
    Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, Bishayee A (2014) Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta (BBA)-Rev Cancer 1845(2):136–154CrossRefGoogle Scholar
  70. 70.
    Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD (1998) How cells respond to interferons. Annu Rev Biochem 67(1):227–264CrossRefPubMedGoogle Scholar
  71. 71.
    Stephanou A, Latchman DS (2003) STAT-1: a novel regulator of apoptosis. Int J Exp Pathol 84(6):239–244CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Su CC, Lin HC, Lin YP, Shan YS, Yang BC (2013) Expression of Th17-related genes in PHA/IL-2-activated human T cells by Fas signaling via caspase-1-and Stat3-dependent pathway. Cell Immunol 281(2):101–110CrossRefPubMedGoogle Scholar
  73. 73.
    Subramaniam A, Shanmugam MK, Perumal E, Li F, Nachiyappan A, Dai X, Hui KM (2013) Potential role of signal transducer and activator of transcription (STAT) 3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. Biochim Biophys Acta (BBA)-Rev Cancer 1835(1):46–60CrossRefGoogle Scholar
  74. 74.
    Takeda K, Akira S (2000) STAT family of transcription factors in cytokine-mediated biological responses. Cytokine Growth Factor Rev 11(3):199–207CrossRefPubMedGoogle Scholar
  75. 75.
    Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Akira S (1997) Targeted disruption of the mouse STAT3 gene leads to early embryonic lethality. Proc Natl Acad Sci 94(8):3801–3804CrossRefPubMedGoogle Scholar
  76. 76.
    Takeda K, Tanaka T, Shi W, Matsumoto M (1996) Essential role of Stat6 in IL-4 signalling. Nature 380(6575):627CrossRefPubMedGoogle Scholar
  77. 77.
    Takemoto S, Ushijima K, Kawano K, Yamaguchi T, Terada A, Fujiyoshi N, Kage M (2009) Expression of activated signal transducer and activator of transcription-3 predicts poor prognosis in cervical squamous-cell carcinoma. Br J Cancer 101(6):967–972CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA (1996) Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382(6587):171CrossRefPubMedGoogle Scholar
  79. 79.
    Tkach M, Rosemblit C, Rivas MA, Proietti CJ, Flaqué MCD, Mercogliano MF, Deza EG (2013) p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of STAT3 and breast cancer growth. Endocr Relat Cancer 20(2):197–212CrossRefPubMedGoogle Scholar
  80. 80.
    Trauzold A, Röder C, Sipos B, Karsten K, Arlt A, Jiang P, Siebert R (2005) CD95 and TRAF2 promote invasiveness of pancreatic cancer cells. FASEB J 19(6):620–622CrossRefPubMedGoogle Scholar
  81. 81.
    Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R (1998) STAT3 activation by Src induces specific gene regulation and is required for cell transformation. Mol Cell Biol 18(5):2545–2552CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Uchiyama T, Takahashi H, Endo H, Sugiyama M, Sakai E, Hosono K, Nakajima A (2011) Role of the long form leptin receptor and of the STAT3 signaling pathway in colorectal cancer progression. Int J Oncol 39(4):935PubMedGoogle Scholar
  83. 83.
    Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Davey HW (1997) Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci 94(14):7239–7244CrossRefPubMedGoogle Scholar
  84. 84.
    Visconti R, Gadina M, Chiariello M, Chen EH, Stancato LF, Gutkind JS, O’Shea JJ (2000) Importance of the MKK6/p38 pathway for interleukin-12–induced STAT4 serine phosphorylation and transcriptional activity. Blood 96(5):1844–1852PubMedGoogle Scholar
  85. 85.
    Walford HH, Doherty TA (2013) STAT6 and lung inflammation. Jak-stat 2(4):e25301CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Wang Y, Qu A, Wang H (2015) Signal transducer and activator of transcription 4 in liver diseases. Int J Biol Sci 11(4):448CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Ward AC, Barry A, O’Sullivan LA (2009) Suppressors of cytokine signaling: functions in normal biology and roles in disease. In: Stephanou A (ed) Jak-stat pathway in disease. Landes Bioscience, Austin, pp 10–23Google Scholar
  88. 88.
    Weidemann A, Johnson RS (2008) Biology of HIF-1α. Cell Death Differ 15(4):621–627CrossRefPubMedGoogle Scholar
  89. 89.
    Wurster AL, Tanaka T, Grusby MJ (2000) The biology of Stat4 and Stat6. Oncogene 19(21):2577CrossRefPubMedGoogle Scholar
  90. 90.
    Yang E, Lerner L, Besser D, Darnell JE (2003) Independent and cooperative activation of chromosomal c-fos promoter by STAT3. J Biol Chem 278(18):15794–15799CrossRefPubMedGoogle Scholar
  91. 91.
    Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR (2007) Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB. Genes Dev 21(11):1396–1408CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Yokogami K, Wakisaka S, Avruch J, Reeves SA (2000) Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Curr Biol 10(1):47–50CrossRefPubMedGoogle Scholar
  93. 93.
    Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Yuan ZL, Guan YJ, Chatterjee D, Chin YE (2005) STAT3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307(5707):269–273CrossRefPubMedGoogle Scholar
  95. 95.
    Zhang J, Zhang D, Hua Z (2004) FADD and its phosphorylation. IUBMB Life 56:395–402CrossRefPubMedGoogle Scholar
  96. 96.
    Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264(5155):95–99CrossRefPubMedGoogle Scholar
  97. 97.
    Zhu MH, John S, Berg M, Leonard WJ (1999) Functional association of Nmi with Stat5 and Stat1 in IL-2-and IFN γ-mediated signaling. Cell 96(1):121–130CrossRefPubMedGoogle Scholar

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© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  1. 1.Department of BiotechnologyRayalaseema UniversityKurnoolIndia

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