Role of STAT3 in Liver Cancer

  • Dongkyoo Park
  • Neha Merchant
  • Inho ChoiEmail author


Hepatocellular carcinoma (HCC) is a malignant cancer that shows heterogeneous etiology and the third leading of cancer-related deaths in the world. In spite of its severity, there is only one systemic chemotherapy drug known as sorafenib showing a valuable effect on a small number of HCC patients. Signal transducers and activators of transcription (STATs), a family of transcription factors, consist of seven members in mammalian cells: STATs 1, 2, 3, 4, 5a, 5b, and 6. STAT transcription factors have a characteristic Src homology 2 (SH2) domain whose function is indispensable to the activation of STAT proteins triggered by Janus kinase (JAK) signaling. Among the STAT transcription factor family, STAT3 performs a vital function in advancement and tumorigenesis because it participates in replicating various proteins that are responsible for angiogenesis, proliferation, invasion, metastasis, and apoptosis. Although the activation of STAT3 is usually transient in normal cells, cancer cells show a positive feed-forward loop that results in the persistent activation of STAT3. The expression and activity of STAT3 are increased in a wide range of malignancies. Although several studies have reported the oncogenic functions, the antitumor effects of STAT3 should be considered carefully in the development of therapeutic methods that target STAT3 signaling. We believe that STAT3 signaling will be a promising target of treatment for HCC patients who need further research of adverse effects or personalized treatment via the modulation of STAT3 signaling.


Hepatocellular carcinoma Signal transducers and activators of transcription Cell proliferation Cell cycle Metastasis 


  1. 1.
    Abroun S, Saki N, Ahmadvand M, Asghari F, Salari F, Rahim F (2015) STATs: an old story, yet mesmerizing. Cell J (Yakhteh) 17(3):395Google Scholar
  2. 2.
    Alas S, Bonavida B (2003) Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin’s lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin Cancer Res 9(1):316–326PubMedGoogle Scholar
  3. 3.
    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):4444–4453PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Bard-Chapeau EA, Li S, Ding J, Zhang SS, Zhu HH, Princen F, Fang DD, Han T, Bailly-Maitre B, Poli V (2011) Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell 19(5):629–639PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Bartoli M, Platt D, Lemtalsi T, Gu X, Brooks SE, Marrero MB, Caldwell RB (2003) VEGF differentially activates STAT3 in microvascular endothelial cells. FASEB J 17(11):1562–1564CrossRefPubMedGoogle Scholar
  6. 6.
    Bockhorn M, Jain RK, Munn LL (2007) Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed? Lancet Oncol 8(5):444–448PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    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
  8. 8.
    Calvisi DF (2011) Dr. Jekyll and Mr. Hyde: a paradoxical oncogenic and tumor suppressive role of signal transducer and activator of transcription 3 in liver cancer. Hepatology 54(1):9–12CrossRefPubMedGoogle Scholar
  9. 9.
    Carpenter RL, Lo H-W (2014) STAT3 target genes relevant to human cancers. Cancer 6(2):897–925CrossRefGoogle Scholar
  10. 10.
    Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernández-Luna JL, Nuñez G (1999) Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10(1):105–115CrossRefPubMedGoogle Scholar
  11. 11.
    Chapman RS, Lourenco PC, Tonner E, Flint DJ, Selbert S, Takeda K, Akira S, Clarke AR, Watson CJ (1999) Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Genes Dev 13(19):2604–2616PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chen Z, Han ZC (2008) STAT3: a critical transcription activator in angiogenesis. Med Res Rev 28(2):185–200CrossRefPubMedGoogle Scholar
  13. 13.
    Cheng A-L, Kang Y-K, Chen Z, Tsao C-J, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang T-S (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10(1):25–34CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chiang SP, Cabrera RM, Segall JE (2016) Tumor cell intravasation. Am J Phys Cell Phys 311(1):C1–C14CrossRefGoogle Scholar
  15. 15.
    Choi H-J, Han J-S (2012) Overexpression of phospholipase D enhances Bcl-2 expression by activating STAT3 through independent activation of ERK and p38MAPK in HeLa cells. Biochim Biophys Acta (BBA) Mol Cell Res 1823(6):1082–1091CrossRefGoogle Scholar
  16. 16.
    Chung J, Uchida E, Grammer TC, Blenis J (1997) STAT3 serine phosphorylation by ERK-dependent and-independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol 17(11):6508–6516PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Chung Y-H, Cho N-H, Garcia MI, Lee S-H, Feng P, Jung JU (2004) Activation of Stat3 transcription factor by Herpesvirus saimiri STP-A oncoprotein. J Virol 78(12):6489–6497PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Conn EM, Botkjaer KA, Kupriyanova TA, Andreasen PA, Deryugina EI, Quigley JP (2009) Comparative analysis of metastasis variants derived from human prostate carcinoma cells: roles in intravasation of VEGF-mediated angiogenesis and uPA-mediated invasion. Am J Pathol 175(4):1638–1652PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    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
  20. 20.
    de la Iglesia N, Konopka G, Puram SV, Chan JA, Bachoo RM, You MJ, Levy DE, DePinho RA, Bonni A (2008) Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev 22(4):449–462PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Debidda M, Wang L, Zang H, Poli V, Zheng Y (2005) A role of STAT3 in Rho GTPase-regulated cell migration and proliferation. J Biol Chem 280(17):17275–17285CrossRefPubMedGoogle Scholar
  22. 22.
    Dechow TN, Pedranzini L, Leitch A, Leslie K, Gerald WL, Linkov I, Bromberg JF (2004) Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc Natl Acad Sci U S A 101(29):10602–10607PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Dong Li H, Huang C, Jian Huang K, Dong Wu W, Jiang T, Cao J, Zhong Feng Z, Jun Qiu Z (2011) STAT3 knockdown reduces pancreatic cancer cell invasiveness and matrix metalloproteinase-7 expression in nude mice. PLoS One 6(10):e25941CrossRefGoogle Scholar
  24. 24.
    Eyking A, Ey B, Rünzi M, Roig AI, Reis H, Schmid KW, Gerken G, Podolsky DK, Cario E (2011) 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(6):2154–2165PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Feng G-S (2012) Conflicting roles of molecules in hepatocarcinogenesis: paradigm or paradox. Cancer Cell 21(2):150–154PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Foshay KM, Gallicano GI (2008) Regulation of Sox2 by STAT3 initiates commitment to the neural precursor cell fate. Stem Cells Dev 17(2):269–278CrossRefPubMedGoogle Scholar
  27. 27.
    Frank DA (2007) STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett 251(2):199–210CrossRefPubMedGoogle Scholar
  28. 28.
    Garcia R, Yu C-L, Hudnall A, Catlett R, Nelson KL, Smithgall T, Fujita DJ, Ethier SP, Jove R (1997) Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ 8(12):1267–1276PubMedGoogle Scholar
  29. 29.
    Germain D, Frank DA (2007) Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res 13(19):5665–5669CrossRefPubMedGoogle Scholar
  30. 30.
    Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE (2009) Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324(5935):1713–1716PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Grivennikov SI (2013) IL-11: a prominent pro-tumorigenic member of the IL-6 family. Cancer Cell 24(2):145–147CrossRefPubMedGoogle Scholar
  32. 32.
    Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D, Johnson RS (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
  33. 33.
    Guo J, Ma Q, Zhou X, Fan P, Shan T, Miao D (2013) Inactivation of p27kip1 promotes chemical hepatocarcinogenesis through enhancing inflammatory cytokine secretion and STAT3 signaling activation. J Cell Physiol 228(10):1967–1976CrossRefPubMedGoogle Scholar
  34. 34.
    Harney AS, Arwert EN, Entenberg D, Wang Y, Guo P, Qian B-Z, Oktay MH, Pollard JW, Jones JG, Condeelis JS (2015) Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2 hi macrophage–derived VEGFA. Cancer Discov 5(9):932–943PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA, Jaeger SA, Ogata H, Karin M, Struhl K, Hadzopoulou-Cladaras M (2011) An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 147(6):1233–1247PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    He G, Yu G-Y, Temkin V, Ogata H, Kuntzen C, Sakurai T, Sieghart W, Peck-Radosavljevic M, Leffert HL, Karin M (2010) Hepatocyte IKKβ/NF-κB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17(3):286–297PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    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):297–314PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Heinrich PC, Behrmann I, Serge H, Hermanns HM, Müller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374(1):1–20PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Herrmann A, Cherryholmes G, Schroeder A, Phallen J, Alizadeh D, Xin H, Wang T, Lee H, Lahtz C, Swiderski P (2014) TLR9 is critical for glioma stem cell maintenance and targeting. Cancer Res 74(18):5218–5228PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Hossain DMS, Dos Santos C, Zhang Q, Kozlowska A, Liu H, Gao C, Moreira D, Swiderski P, Jozwiak A, Kline J (2014) Leukemia cell–targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity. Blood 123(1):15–25PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Hwang JH, Kim DW, Suh JM, Kim H, Song JH, Hwang ES, Park KC, Chung HK, Kim JM, Lee T-H (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):1155–1166CrossRefPubMedGoogle Scholar
  42. 42.
    Ilaria RL, Van Etten RA (1996) P210 and P190BCR/ABL induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem 271(49):31704–31710CrossRefPubMedGoogle Scholar
  43. 43.
    Itoh M, Murata T, Suzuki T, Shindoh M, Nakajima K, Imai K, Yoshida K (2006) Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells. Oncogene 25(8):1195–1204CrossRefPubMedGoogle Scholar
  44. 44.
    Jain N, Zhang T, Kee WH, Li W, Cao X (1999) Protein kinase C δ associates with and phosphorylates Stat3 in an interleukin-6-dependent manner. J Biol Chem 274(34):24392–24400CrossRefPubMedGoogle Scholar
  45. 45.
    Jiang R, Tan Z, Deng L, Chen Y, Xia Y, Gao Y, Wang X, Sun B (2011) Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology 54(3):900–909CrossRefPubMedGoogle Scholar
  46. 46.
    Kamran MZ, Patil P, Gude RP (2013) Role of STAT3 in cancer metastasis and translational advances. BioMed Res Int 2013:421821PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Kiuchi N, Nakajima K, Ichiba M, Fukada T, Narimatsu M, Mizuno K, Hibi M, Hirano T (1999) STAT3 is required for the gp130-mediated full activation of the c-myc gene. J Exp Med 189(1):63–73PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Klemm JD, Schreiber SL, Crabtree GR (1998) Dimerization as a regulatory mechanism in signal transduction. Annu Rev Immunol 16(1):569–592CrossRefPubMedGoogle Scholar
  49. 49.
    Kojima H, Sasaki T, Ishitani T, Iemura S-I, Zhao H, Kaneko S, Kunimoto H, Natsume T, Matsumoto K, Nakajima K (2005) STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFβ-activated kinase 1 for STAT3 Ser-727 phosphorylation. Proc Natl Acad Sci U S A 102(12):4524–4529PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Leaman DW, Leung S, Li X, Stark GR (1996) Regulation of STAT-dependent pathways by growth factors and cytokines. FASEB J 10(14):1578–1588CrossRefPubMedGoogle Scholar
  51. 51.
    Leeman RJ, Lui VWY, Grandis JR (2006) STAT3 as a therapeutic target in head and neck cancer. Expert Opin Biol Ther 6(3):231–241CrossRefPubMedGoogle Scholar
  52. 52.
    Leslie K, Lang C, Devgan G, Azare J, Berishaj M, Gerald W, Kim YB, Paz K, Darnell JE, Albanese C (2006) Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res 66(5):2544–2552CrossRefPubMedGoogle Scholar
  53. 53.
    Li L, Hooi D, Chhabra SR, Pritchard D, Shaw PE (2004) Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3. Oncogene 23(28):4894–4902CrossRefPubMedGoogle Scholar
  54. 54.
    Liby K, Voong N, Williams CR, Risingsong R, Royce DB, Honda T, Gribble GW, Sporn MB, Letterio JJ (2006) The synthetic triterpenoid CDDO-Imidazolide suppresses STAT phosphorylation and induces apoptosis in myeloma and lung cancer cells. Clin Cancer Res 12(14):4288–4293CrossRefPubMedGoogle Scholar
  55. 55.
    Lin L, Amin R, Gallicano G, Glasgow E, Jogunoori W, Jessup J, Zasloff M, Marshall J, Shetty K, Johnson L (2009) The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling. Oncogene 28(7):961–972PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, de Oliveira AC, Santoro A, Raoul J-L, Forner A (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    McCarty OJ, Mousa SA, Bray PF, Konstantopoulos K (2000) Immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions. Blood 96(5):1789–1797PubMedGoogle Scholar
  58. 58.
    Miranda C, Fumagalli T, Anania MC, Vizioli MG, Pagliardini S, Pierotti MA, Greco A (2010) Role of STAT3 in in vitro transformation triggered by TRK oncogenes. PLoS One 5(3):e9446PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Ng DCH, Lin BH, Lim CP, Huang G, Zhang T, Poli V, Cao X (2006) Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin. J Cell Biol 172(2):245–257PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Nguyen DX, Bos PD, Massagué J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9(4):274–284CrossRefGoogle Scholar
  61. 61.
    Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21(13):2000–2008CrossRefPubMedGoogle Scholar
  62. 62.
    Niu G, Wright KL, Ma Y, Wright GM, Huang M, Irby R, Briggs J, Karras J, Cress WD, Pardoll D (2005) Role of Stat3 in regulating p53 expression and function. Mol Cell Biol 25(17):7432–7440PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    O’Sullivan KE, Reynolds JV, O’Hanlon C, O’Sullivan JN, Lysaght J (2014) Could signal transducer and activator of transcription 3 be a therapeutic target in obesity-related gastrointestinal malignancy? J Gastrointest Cancer 45(1):1–11CrossRefPubMedGoogle Scholar
  64. 64.
    Oh M-K, Park H-J, Kim N-H, Park S-J, Park I-Y, Kim I-S (2011) Hypoxia-inducible factor-1α enhances haptoglobin gene expression by improving binding of STAT3 to the promoter. J Biol Chem 286(11):8857–8865PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Park EJ, Lee JH, Yu G-Y, He G, Ali SR, Holzer RG, Österreicher CH, Takahashi H, Karin M (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140(2):197–208PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Portai C, De Amici M, Quaglini S, Paglino C, Tagliani F, Boncimino A, Moratti R, Corazza G (2008) Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma. Ann Oncol 19(2):353–358CrossRefGoogle Scholar
  67. 67.
    Putoczki TL, Thiem S, Loving A, Busuttil RA, Wilson NJ, Ziegler PK, Nguyen PM, Preaudet A, Farid R, Edwards KM (2013) Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell 24(2):257–271CrossRefPubMedGoogle Scholar
  68. 68.
    Qiu Z, Huang C, Sun J, Qiu W, Zhang J, Li H, Jiang T, Huang K, Cao J (2007) RNA interference-mediated signal transducers and activators of transcription 3 gene silencing inhibits invasion and metastasis of human pancreatic cancer cells. Cancer Sci 98(7):1099–1106PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Ram PT, Iyengar R (2001) G protein coupled receptor signaling through the Src and Stat3 pathway: role in proliferation and transformation. Oncogene 20(13):1601–1606CrossRefPubMedGoogle Scholar
  70. 70.
    Rane SG, Reddy EP (2000) Janus kinases: components of multiple signaling pathways. Oncogene 19(49):5662–5679CrossRefPubMedGoogle Scholar
  71. 71.
    Rebouissou S, Amessou M, Couchy G, Poussin K, Imbeaud S, Pilati C, Izard T, Balabaud C, Bioulac-Sage P, Zucman-Rossi J (2009) Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457(7226):200–204CrossRefPubMedGoogle Scholar
  72. 72.
    Reich NC, Liu L (2006) Tracking STAT nuclear traffic. Nat Rev Immunol 6(8):602–612CrossRefPubMedGoogle Scholar
  73. 73.
    Riehle KJ, Campbell JS, McMahan RS, Johnson MM, Beyer RP, Bammler TK, Fausto N (2008) Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3. J Exp Med 205(1):91–103PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Rocha S, Campbell KJ, Perkins ND (2003) p53-and Mdm2-independent repression of NF-κB transactivation by the ARF tumor suppressor. Mol Cell 12(1):15–25CrossRefPubMedGoogle Scholar
  75. 75.
    Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H, Yoshikawa K, Akira S, Takeda J (1999) Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J 18(17):4657–4668PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Schneller D, Machat G, Sousek A, Proell V, van Zijl F, Zulehner G, Huber H, Mair M, Muellner MK, Nijman S (2011) p19ARF/p14ARF controls oncogenic functions of signal transducer and activator of transcription 3 in hepatocellular carcinoma. Hepatology 54(1):164–172CrossRefPubMedGoogle Scholar
  77. 77.
    Schwabe RF, Wang TC (2011) Targeting liver cancer: first steps toward a miRacle? Cancer Cell 20(6):698–699PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732CrossRefGoogle Scholar
  79. 79.
    Silva CM (2004) Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 23(48):8017–8023CrossRefPubMedGoogle Scholar
  80. 80.
    Silver DL, Naora H, Liu J, Cheng W, Montell DJ (2004) Activated signal transducer and activator of transcription (STAT) 3. Cancer Res 64(10):3550–3558CrossRefPubMedGoogle Scholar
  81. 81.
    Suiqing C, Min Z, Lirong C (2005) Overexpression of phosphorylated-STAT3 correlated with the invasion and metastasis of cutaneous squamous cell carcinoma. J Dermatol 32(5):354–360CrossRefPubMedGoogle Scholar
  82. 82.
    Svinka J, Mikulits W, Eferl R (2014) STAT3 in hepatocellular carcinoma: new perspectives. Hepatic Oncol 1(1):107–120CrossRefGoogle Scholar
  83. 83.
    Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T, Kishimoto T (1989) Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58(3):573–581CrossRefPubMedGoogle Scholar
  84. 84.
    Teng TS, Lin B, Manser E, Ng DCH, Cao X (2009) Stat3 promotes directional cell migration by regulating Rac1 activity via its activator βPIX. J Cell Sci 122(22):4150–4159CrossRefPubMedGoogle Scholar
  85. 85.
    Terry K, Copur MS (2013) Molecular targeted therapy of hepatocellular carcinoma. J Cancer Ther 4(02):426CrossRefGoogle Scholar
  86. 86.
    Turkson J, Bowman T, Adnane J, Zhang Y, Djeu JY, Sekharam M, Frank DA, Holzman LB, Wu J, Sebti S (1999) Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein. Mol Cell Biol 19(11):7519–7528PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    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):2545–2552PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Tye H, Kennedy CL, Najdovska M, McLeod L, McCormack W, Hughes N, Dev A, Sievert W, Ooi CH, Ishikawa T-O (2012) STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell 22(4):466–478CrossRefPubMedGoogle Scholar
  89. 89.
    Vultur A, Arulanandam R, Turkson J, Niu G, Jove R, Raptis L (2005) Stat3 is required for full neoplastic transformation by the simian virus 40 large tumor antigen. Mol Biol Cell 16(8):3832–3846PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Wang H, Lafdil F, Wang L, Park O, Yin S, Niu J, Miller AM, Sun Z, Gao B (2011) Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis. Am J Pathol 179(2):714–724PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10(1):48–54CrossRefPubMedGoogle Scholar
  92. 92.
    Wegrzyn J, Potla R, Chwae Y-J, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A (2009) Function of mitochondrial Stat3 in cellular respiration. Science 323(5915):793–797PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL (2003) Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22(3):319–329PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Wu W-Y, Li J, Wu Z-S, Zhang C-L, Meng X-L (2011) STAT3 activation in monocytes accelerates liver cancer progression. BMC Cancer 11(1):506PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Xie T-X, Wei D, Liu M, Gao AC, Ali-Osman F, Sawaya R, Huang S (2004) Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 23(20):3550–3560CrossRefPubMedGoogle Scholar
  96. 96.
    Xiong A, Yang Z, Shen Y, Zhou J, Shen Q (2014) Transcription factor STAT3 as a novel molecular target for cancer prevention. Cancer 6(2):926–957CrossRefGoogle Scholar
  97. 97.
    Xu Q, Briggs J, Park S, Niu G, Kortylewski M, Zhang S, Gritsko T, Turkson J, Kay H, Semenza GL (2005) Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 24(36):5552–5560CrossRefPubMedGoogle Scholar
  98. 98.
    Yahata Y, Shirakata Y, Tokumaru S, Yamasaki K, Sayama K, Hanakawa Y, Detmar M, Hashimoto K (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):40026–40031CrossRefPubMedGoogle Scholar
  99. 99.
    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
  100. 100.
    Yoshida T, Hanada T, Tokuhisa T, Kosai K-I, Sata M, Kohara M, Yoshimura A (2002) Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation. J Exp Med 196(5):641–653PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Yu C-L, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R (1992) Sta t3-Rela ted protein in cells transformed by the Src oncoprotein. Proc Natl Acad Sci U S A 89:8813CrossRefGoogle Scholar
  102. 102.
    Yu C-Y, Wang L, Khaletskiy A, Farrar WL, Larner A, Colburn NH, Li JJ (2002) STAT3 activation is required for interleukin-6 induced transformation in tumor-promotion sensitive mouse skin epithelial cells. Oncogene 21(25):3949–3960CrossRefPubMedGoogle Scholar
  103. 103.
    Yu H, Lee H, Herrmann A, Buettner R, Jove R (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14(11):736–746CrossRefPubMedGoogle Scholar
  104. 104.
    Yuan Z-L, Guan Y-J, Chatterjee D, Chin YE (2005) Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307(5707):269–273CrossRefPubMedGoogle Scholar
  105. 105.
    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

Copyright information

© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  1. 1.Department of Radiation Oncology, College of Medicine, Winship Cancer InstituteEmory UniversityAtlantaUSA
  2. 2.Department of Hematology and Medical Oncology, Winship Cancer InstituteEmory UniversityAtlantaUSA
  3. 3.Department of Pharmaceutical Engineering, College of Life and Health SciencesHoseo UniversityAsanRepublic of Korea

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