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Journal of Gastrointestinal Cancer

, Volume 48, Issue 3, pp 225–237 | Cite as

Signaling Pathways as Potential Therapeutic Targets in Hepatocarcinogenesis

  • Yeliz Yılmaz
  • Ayşim Güneş
  • Hande Topel
  • Neşe AtabeyEmail author
Review Article
  • 136 Downloads

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and has a poor prognosis. HCC is described as a process with a complex molecular pathogenesis. There are three common mechanisms in the initiation of HCC: (i) liver injury, which is induced by etiologic factors such as chronic viral infections with hepatitis B and hepatitis C viruses, alcohol consumption, and obesity; (ii) fibrosis and cirrhosis, which are triggered after recurrent damage and regeneration cycles; and (iii) de-regulation of one or more oncogene and/or tumor suppressor gene [1, 2, 3, 4, 5].

Surgical resection, liver transplantation, radiofrequency ablation, and trans-catheter arterial chemo­embolization (TACE) are the primary treatment methods for HCC patients. However, only 20% of patients are diagnosed at early stage of HCC and curative treatment options provide low survival rate estimated less than 5 years. In addition, hypervascularization, inflammation, fibrosis, and...

References

  1. 1.
    Guthle M, Dollinger MM. Epidemiology and risk factors of hepatocellular carcinoma. Radiologe. 2014;54(7):654–9. doi: 10.1007/s00117-014-2650-6.CrossRefPubMedGoogle Scholar
  2. 2.
    Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma. Nature Reviews Disease Primers. 2016;2:16018. doi: 10.1038/nrdp.2016.18.CrossRefPubMedGoogle Scholar
  3. 3.
    Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology. 2011;140(5):1410–26. doi: 10.1053/j.gastro.2011.03.006.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118–27. doi: 10.1056/NEJMra1001683.CrossRefGoogle Scholar
  5. 5.
    Fattovich G, Stroffolini T, Zagni I, Donato F (2004) Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (5 Suppl 1):S35-50. doi:S0016508504015938.Google Scholar
  6. 6.
    Bruix J. Liver cancer: still a long way to go. Hepatology. 2011;54(1):1–2. doi: 10.1002/hep.24468.CrossRefPubMedGoogle Scholar
  7. 7.
    EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma (2012). J Hepatol 56 (4):908–943. doi: 10.1016/j.jhep.2011.12.001.
  8. 8.
    Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66. doi: 10.1016/S0140-6736(16)32453-9.CrossRefGoogle Scholar
  9. 9.
    Bishayee A. The role of inflammation and liver cancer. Adv Exp Med Biol. 2014;816:401–35. doi: 10.1007/978-3-0348-0837-8_16.CrossRefPubMedGoogle Scholar
  10. 10.
    Takaki A, Yamamoto K. Control of oxidative stress in hepatocellular carcinoma: helpful or harmful? World J Hepatol. 2015;7(7):968–79. doi: 10.4254/wjh.v7.i7.968.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14(3):181–94. doi: 10.1038/nri3623 nri3623.CrossRefPubMedGoogle Scholar
  12. 12.
    Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Med. 1998;49:407–24. doi: 10.1146/annurev.med.49.1.407.CrossRefPubMedGoogle Scholar
  13. 13.
    Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol. 2005;23(27):6657–63. doi: 10.1200/JCO.2005.14.696.CrossRefPubMedGoogle Scholar
  14. 14.
    Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7(7):505–16. doi: 10.1038/nrm1962.CrossRefPubMedGoogle Scholar
  15. 15.
    Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003;284(1):31–53.CrossRefGoogle Scholar
  16. 16.
    Perugorria MJ, Latasa MU, Nicou A, Cartagena-Lirola H, Castillo J, Goni S, et al. The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis. Hepatology. 2008;48(4):1251–61. doi: 10.1002/hep.22437.CrossRefGoogle Scholar
  17. 17.
    Berasain C, Perugorria MJ, Latasa MU, Castillo J, Goni S, Santamaria M, et al. The epidermal growth factor receptor: a link between inflammation and liver cancer. Exp Biol Med. 2009;234(7):713–25. doi: 10.3181/0901-MR-12.CrossRefGoogle Scholar
  18. 18.
    Papetti M, Herman IM. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol. 2002;282(5):C947–70. doi: 10.1152/ajpcell.00389.2001.CrossRefPubMedGoogle Scholar
  19. 19.
    Kin M, Torimura T, Ueno T, Inuzuka S, Tanikawa K. Sinusoidal capillarization in small hepatocellular carcinoma. Pathol Int. 1994;44(10–11):771–8.PubMedGoogle Scholar
  20. 20.
    Ferrara N. The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS. 2005;94:209–31.Google Scholar
  21. 21.
    Raskopf E, Vogt A, Sauerbruch T, Schmitz V. siRNA targeting VEGF inhibits hepatocellular carcinoma growth and tumor angiogenesis in vivo. J Hepatol. 2008;49(6):977–84. doi: 10.1016/j.jhep.2008.07.022.CrossRefPubMedGoogle Scholar
  22. 22.
    Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, et al. Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology. 2002;35(4):834–42. doi: 10.1053/jhep.2002.32541.CrossRefPubMedGoogle Scholar
  23. 23.
    Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015;4(3):215–66. doi: 10.1002/wdev.176.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10(2):116–29. doi: 10.1038/nrc2780 nrc2780.CrossRefPubMedGoogle Scholar
  25. 25.
    Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, et al. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem. 2007;282(37):26687–95. doi: 10.1074/jbc.M704165200.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Tsunematsu H, Tatsumi T, Kohga K, Yamamoto M, Aketa H, Miyagi T, et al. Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells. Int J Cancer. 2012;130(2):356–64. doi: 10.1002/ijc.26003.CrossRefPubMedGoogle Scholar
  27. 27.
    Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8(3):235–53. doi: 10.1038/nrd2792.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Rajalingam K, Schreck R, Rapp UR, Albert S. Ras oncogenes and their downstream targets. Biochim Biophys Acta. 2007;1773(8):1177–95. doi: 10.1016/j.bbamcr.2007.01.012.CrossRefPubMedGoogle Scholar
  29. 29.
    Ito Y, Sasaki Y, Horimoto M, Wada S, Tanaka Y, Kasahara A, et al. Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology. 1998;27(4):951–8. doi: 10.1002/hep.510270409.CrossRefPubMedGoogle Scholar
  30. 30.
    Schmidt CM, McKillop IH, Cahill PA, Sitzmann JV. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun. 1997;236(1):54–8. doi: 10.1006/bbrc.1997.6840.CrossRefPubMedGoogle Scholar
  31. 31.
    McKillop IH, Schmidt CM, Cahill PA, Sitzmann JV. Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma. Hepatology. 1997;26(6):1484–91. doi: 10.1002/hep.510260615.CrossRefPubMedGoogle Scholar
  32. 32.
    Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, Basecke J, Stivala F, Donia M, Fagone P, Malaponte G, Mazzarino MC, Nicoletti F, Libra M, Maksimovic-Ivanic D, Mijatovic S, Montalto G, Cervello M, Laidler P, Milella M, Tafuri A, Bonati A, Evangelisti C, Cocco L, Martelli AM, McCubrey JA (2011) Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2 (3):135-164. doi: 10.18632/oncotarget.240.
  33. 33.
    Maurer G, Tarkowski B, Baccarini M. Raf kinases in cancer-roles and therapeutic opportunities. Oncogene. 2011;30(32):3477–88. doi: 10.1038/onc.2011.160.CrossRefPubMedGoogle Scholar
  34. 34.
    Ballif BA, Blenis J. Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals. Cell Growth Differ. 2001;12(8):397–408.PubMedGoogle Scholar
  35. 35.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi: 10.1016/j.cell.2011.02.013.CrossRefGoogle Scholar
  36. 36.
    Wu XZ, Xie GR, Chen D. Hypoxia and hepatocellular carcinoma: the therapeutic target for hepatocellular carcinoma. J Gastroenterol Hepatol. 2007;22(8):1178–82. doi: 10.1111/j.1440-1746.2007.04997.x.CrossRefPubMedGoogle Scholar
  37. 37.
    Mazure NM, Chen EY, Yeh P, Laderoute KR, Giaccia AJ. Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer Res. 1996;56(15):3436–40.PubMedGoogle Scholar
  38. 38.
    Sheta EA, Trout H, Gildea JJ, Harding MA, Theodorescu D. Cell density mediated pericellular hypoxia leads to induction of HIF-1alpha via nitric oxide and Ras/MAP kinase mediated signaling pathways. Oncogene. 2001;20(52):7624–34. doi: 10.1038/sj.onc.1204972.CrossRefPubMedGoogle Scholar
  39. 39.
    Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294(5545):1337–40. doi: 10.1126/science.1066373.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998;12(2):149–62.CrossRefGoogle Scholar
  41. 41.
    Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7(2):131–42. doi: 10.1038/nrm1835.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Zhang Q, Bai X, Chen W, Ma T, Hu Q, Liang C, et al. Wnt/beta-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1alpha signaling. Carcinogenesis. 2013;34(5):962–73. doi: 10.1093/carcin/bgt027.CrossRefPubMedGoogle Scholar
  43. 43.
    Ye LY, Chen W, Bai XL, Xu XY, Zhang Q, Xia XF, et al. Hypoxia-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis. Cancer Res. 2016;76(4):818–30. doi: 10.1158/0008-5472.CAN-15-0977.CrossRefPubMedGoogle Scholar
  44. 44.
    Schlaepfer DD, Hunter T. Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src. J Biol Chem. 1997;272(20):13189–95.CrossRefGoogle Scholar
  45. 45.
    Poon RT, Lau C, Pang R, Ng KK, Yuen J, Fan ST. High serum vascular endothelial growth factor levels predict poor prognosis after radiofrequency ablation of hepatocellular carcinoma: importance of tumor biomarker in ablative therapies. Ann Surg Oncol. 2007;14(6):1835–45. doi: 10.1245/s10434-007-9366-z.CrossRefPubMedGoogle Scholar
  46. 46.
    Poon RT, Lau CP, Ho JW, Yu WC, Fan ST, Wong J. Tissue factor expression correlates with tumor angiogenesis and invasiveness in human hepatocellular carcinoma. Clin Cancer Res. 2003;9(14):5339–45.PubMedGoogle Scholar
  47. 47.
    Dhar DK, Naora H, Yamanoi A, Ono T, Kohno H, Otani H, et al. Requisite role of VEGF receptors in angiogenesis of hepatocellular carcinoma: a comparison with angiopoietin/tie pathway. Anticancer Res. 2002;22(1A):379–86.PubMedGoogle Scholar
  48. 48.
    Schmitt M, Horbach A, Kubitz R, Frilling A, Haussinger D. Disruption of hepatocellular tight junctions by vascular endothelial growth factor (VEGF): a novel mechanism for tumor invasion. J Hepatol. 2004;41(2):274–83. doi: 10.1016/j.jhep.2004.04.035.CrossRefPubMedGoogle Scholar
  49. 49.
    Ueda S, Basaki Y, Yoshie M, Ogawa K, Sakisaka S, Kuwano M, et al. PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib. Cancer Res. 2006;66(10):5346–53. doi: 10.1158/0008-5472.CAN-05-3684.CrossRefPubMedGoogle Scholar
  50. 50.
    Griffiths L, Stratford IJ. Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumour growth and response to therapy. Br J Cancer. 1997;76(6):689–93.CrossRefGoogle Scholar
  51. 51.
    Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, Thorgeirsson SS. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci USA. 2004;101(13):4477–82. doi: 10.1073/pnas.0306068101.CrossRefGoogle Scholar
  52. 52.
    Tavian D, De Petro G, Benetti A, Portolani N, Giulini SM, Barlati S. u-PA and c-MET mRNA expression is co-ordinately enhanced while hepatocyte growth factor mRNA is down-regulated in human hepatocellular carcinoma. Int J Cancer. 2000;87(5):644–9.CrossRefGoogle Scholar
  53. 53.
    Goyal L, Muzumdar MD, Zhu AX. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin Cancer Res. 2013;19(9):2310–8. doi: 10.1158/1078-0432.CCR-12-2791.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. Targeting MET in cancer: rationale and progress. Nat Rev Cancer. 2012;12(2):89–103. doi: 10.1038/nrc3205.CrossRefPubMedGoogle Scholar
  55. 55.
    DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2(5):e1600200. doi: 10.1126/sciadv.1600200.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Amann T, Maegdefrau U, Hartmann A, Agaimy A, Marienhagen J, Weiss TS, et al. GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis. Am J Pathol. 2009;174(4):1544–52. doi: 10.2353/ajpath.2009.080596.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Daskalow K, Pfander D, Weichert W, Rohwer N, Thelen A, Neuhaus P, et al. Distinct temporospatial expression patterns of glycolysis-related proteins in human hepatocellular carcinoma. Histochem Cell Biol. 2009;132(1):21–31. doi: 10.1007/s00418-009-0590-4.CrossRefPubMedGoogle Scholar
  58. 58.
    Gong L, Cui Z, Chen P, Han H, Peng J, Leng X. Reduced survival of patients with hepatocellular carcinoma expressing hexokinase II. Med Oncol. 2012;29(2):909–14. doi: 10.1007/s12032-011-9841-z.CrossRefPubMedGoogle Scholar
  59. 59.
    Chen Z, Lu X, Wang Z, Jin G, Wang Q, Chen D, Chen T, Li J, Fan J, Cong W, Gao Q, He X (2015) Co-expression of PKM2 and TRIM35 predicts survival and recurrence in hepatocellular carcinoma. Oncotarget 6 (4):2538-2548. doi:  10.18632/oncotarget.2991.
  60. 60.
    Shang RZ, Qu SB, Wang DS. Reprogramming of glucose metabolism in hepatocellular carcinoma: progress and prospects. World J Gastroenterol. 2016;22(45):9933–43. doi: 10.3748/wjg.v22.i45.9933.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Mertens C, Darnell JE Jr. SnapShot: JAK-STAT signaling. Cell. 2007;131(3):612. doi: 10.1016/j.cell.2007.10.033.CrossRefPubMedGoogle Scholar
  62. 62.
    Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, et al. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013;23(9):1422–33. doi: 10.1101/gr.154492.113.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Shibata T, Aburatani H. Exploration of liver cancer genomes. Nat Rev Gastroenterol Hepatol. 2014;11(6):340–9. doi: 10.1038/nrgastro.2014.6.CrossRefPubMedGoogle Scholar
  64. 64.
    Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140(2):197–208. doi: 10.1016/j.cell.2009.12.052.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    He G, Karin M. NF-kappaB and STAT3—key players in liver inflammation and cancer. Cell Res. 2011;21(1):159–68. doi: 10.1038/cr.2010.183.CrossRefGoogle Scholar
  66. 66.
    Wang Y, Qu A, Wang H. Signal transducer and activator of transcription 4 in liver diseases. Int J Biol Sci. 2015;11(4):448–55. doi: 10.7150/ijbs.11164.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Yang W, Lu Y, Xu Y, Xu L, Zheng W, Wu Y, et al. Estrogen represses hepatocellular carcinoma (HCC) growth via inhibiting alternative activation of tumor-associated macrophages (TAMs). J Biol Chem. 2012;287(48):40140–9. doi: 10.1074/jbc.M112.348763.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Farber-Katz SE, Dippold HC, Buschman MD, Peterman MC, Xing M, Noakes CJ, et al. DNA damage triggers Golgi dispersal via DNA-PK and GOLPH3. Cell. 2014;156(3):413–27. doi: 10.1016/j.cell.2013.12.023.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Goodwin JF, Knudsen KE. Beyond DNA repair: DNA-PK function in cancer. Cancer Discov. 2014;4(10):1126–39. doi: 10.1158/2159-8290.cd-14-0358.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Pascale RM, Joseph C, Latte G, Evert M, Feo F, Calvisi DF. DNA-PKcs: a promising therapeutic target in human hepatocellular carcinoma? DNA Repair (Amst). 2016;47:12–20. doi: 10.1016/j.dnarep.2016.10.004.CrossRefGoogle Scholar
  71. 71.
    Zou LH, Shang ZF, Tan W, Liu XD, Xu QZ, Song M, Wang Y, Guan H, Zhang SM, Yu L, Zhong CG, Zhou PK (2015) TNKS1BP1 functions in DNA double-strand break repair though facilitating DNA-PKcs autophosphorylation dependent on PARP-1. Oncotarget 6 (9):7011-7022. doi: 10.18632/oncotarget.3137.
  72. 72.
    Evert M, Frau M, Tomasi ML, Latte G, Simile MM, Seddaiu MA, et al. Deregulation of DNA-dependent protein kinase catalytic subunit contributes to human hepatocarcinogenesis development and has a putative prognostic value. Br J Cancer. 2013;109(10):2654–64. doi: 10.1038/bjc.2013.606.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Cornell L, Munck JM, Alsinet C, Villanueva A, Ogle L, Willoughby CE, et al. DNA-PK-A candidate driver of hepatocarcinogenesis and tissue biomarker that predicts response to treatment and survival. Clin Cancer Res. 2015;21(4):925–33. doi: 10.1158/1078-0432.ccr-14-0842.CrossRefPubMedGoogle Scholar
  74. 74.
    Leu JI, George DL. Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria. Genes Dev. 2007;21(23):3095–109. doi: 10.1101/gad.1567107.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, et al. Non-cell-autonomous tumor suppression by p53. Cell. 2013;153(2):449–60. doi: 10.1016/j.cell.2013.03.020.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Amaral JD, Castro RE, Steer CJ, Rodrigues CM. p53 and the regulation of hepatocyte apoptosis: implications for disease pathogenesis. Trends Mol Med. 2009;15(11):531–41. doi: 10.1016/j.molmed.2009.09.005.CrossRefPubMedGoogle Scholar
  77. 77.
    Meng X, Franklin DA, Dong J, Zhang Y. MDM2-p53 pathway in hepatocellular carcinoma. Cancer Res. 2014;74(24):7161–7. doi: 10.1158/0008-5472.can-14-1446.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Brown CJ, Cheok CF, Verma CS, Lane DP. Reactivation of p53: from peptides to small molecules. Trends Pharmacol Sci. 2011;32(1):53–62. doi: 10.1016/j.tips.2010.11.004.CrossRefPubMedGoogle Scholar
  79. 79.
    Muller PA, Vousden KH. p53 mutations in cancer. Nat Cell Biol. 2013;15(1):2–8. doi: 10.1038/ncb2641.CrossRefPubMedGoogle Scholar
  80. 80.
    Pietsch EC, Sykes SM, McMahon SB, Murphy ME. The p53 family and programmed cell death. Oncogene. 2008;27(50):6507–21. doi: 10.1038/onc.2008.315.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Louandre C, Marcq I, Bouhlal H, Lachaier E, Godin C, Saidak Z, Francois C, Chatelain D, Debuysscher V, Barbare JC, Chauffert B, Galmiche A (2015) The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett 356 (2 Pt B):971-977. doi: 10.1016/j.canlet.2014.11.014.CrossRefGoogle Scholar
  82. 82.
    Ozturk M, Arslan-Ergul A, Bagislar S, Senturk S, Yuzugullu H. Senescence and immortality in hepatocellular carcinoma. Cancer Lett. 2009;286(1):103–13. doi: 10.1016/j.canlet.2008.10.048.CrossRefPubMedGoogle Scholar
  83. 83.
    Ilagan MX, Kopan R. SnapShot: notch signaling pathway. Cell. 2007;128(6):1246. doi: 10.1016/j.cell.2007.03.011.CrossRefPubMedGoogle Scholar
  84. 84.
    Katsube K, Sakamoto K. Notch in vertebrates—molecular aspects of the signal. Int J Dev Biol. 2005;49(2–3):369–74. doi: 10.1387/ijdb.041950kk.CrossRefPubMedGoogle Scholar
  85. 85.
    D'Souza B, Meloty-Kapella L, Weinmaster G. Canonical and non-canonical Notch ligands. Curr Top Dev Biol. 2010;92:73–129. doi: 10.1016/s0070-2153(10)92003-6.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216–33. doi: 10.1016/j.cell.2009.03.045.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Tanimizu N, Miyajima A. Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors. J Cell Sci. 2004;117(Pt 15):3165–74. doi: 10.1242/jcs.01169.CrossRefPubMedGoogle Scholar
  88. 88.
    Fiorotto R, Raizner A, Morell CM, Torsello B, Scirpo R, Fabris L, et al. Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. J Hepatol. 2013;59(1):124–30. doi: 10.1016/j.jhep.2013.02.025.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Morell CM, Fiorotto R, Fabris L, Strazzabosco M. Notch signalling beyond liver development: emerging concepts in liver repair and oncogenesis. Clin Res Hepatol Gastroenterol. 2013;37(5):447–54. doi: 10.1016/j.clinre.2013.05.008.CrossRefPubMedGoogle Scholar
  90. 90.
    Gramantieri L, Giovannini C, Lanzi A, Chieco P, Ravaioli M, Venturi A, et al. Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma. Liver Int. 2007;27(7):997–1007. doi: 10.1111/j.1478-3231.2007.01544.x.CrossRefPubMedGoogle Scholar
  91. 91.
    Gil-Garcia B, Baladron V. The complex role of NOTCH receptors and their ligands in the development of hepatoblastoma, cholangiocarcinoma and hepatocellular carcinoma. Biol Cell. 2016;108(2):29–40. doi: 10.1111/boc.201500029.CrossRefPubMedGoogle Scholar
  92. 92.
    Villanueva A, Alsinet C, Yanger K, Hoshida Y, Zong Y, Toffanin S, et al. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology. 2012;143(6):1660–1669 e1667. doi: 10.1053/j.gastro.2012.09.002.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Luo J, Wang P, Wang R, Wang J, Liu M, Xiong S, Li Y, Cheng B (2016) The Notch pathway promotes the cancer stem cell characteristics of CD90+ cells in hepatocellular carcinoma. Oncotarget 7 (8):9525-9537. doi: 10.18632/oncotarget.6672.
  94. 94.
    Amakye D, Jagani Z, Dorsch M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat Med. 2013;19(11):1410–22. doi: 10.1038/nm.3389.CrossRefPubMedGoogle Scholar
  95. 95.
    Chen MH, Wilson CW, Chuang PT. SnapShot: hedgehog signaling pathway. Cell. 2007;130(2):386. doi: 10.1016/j.cell.2007.07.017.CrossRefPubMedGoogle Scholar
  96. 96.
    Zheng X, Vittar NB, Gai X, Fernandez-Barrena MG, Moser CD, Hu C, et al. The transcription factor GLI1 mediates TGFbeta1 driven EMT in hepatocellular carcinoma via a SNAI1-dependent mechanism. PLoS One. 2012;7(11):e49581. doi: 10.1371/journal.pone.0049581.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Wang Y, Han C, Lu L, Magliato S, Wu T. Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology. 2013;58(3):995–1010. doi: 10.1002/hep.26394.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Lu JT, Zhao WD, He W, Wei W. Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway. Acta Pharmacol Sin. 2012;33(5):691–700. doi: 10.1038/aps.2012.24.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Xu QR, Zheng X, Zan XF, Yao YM, Yang W, Liu QG (2012) [Gli1 expression and its relationship with the expression of Shh, Vimentin and E-cadherin in human hepatocellular carcinoma]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 28 (5):536–539.Google Scholar
  100. 100.
    Sicklick JK, Li YX, Jayaraman A, Kannangai R, Qi Y, Vivekanandan P, et al. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis. 2006;27(4):748–57. doi: 10.1093/carcin/bgi292.CrossRefPubMedGoogle Scholar
  101. 101.
    Tada M, Kanai F, Tanaka Y, Tateishi K, Ohta M, Asaoka Y, et al. Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clin Cancer Res. 2008;14(12):3768–76. doi: 10.1158/1078-0432.ccr-07-1181.CrossRefPubMedGoogle Scholar
  102. 102.
    Chan IS, Guy CD, Chen Y, Lu J, Swiderska-Syn M, Michelotti GA, et al. Paracrine Hedgehog signaling drives metabolic changes in hepatocellular carcinoma. Cancer Res. 2012;72(24):6344–50. doi: 10.1158/0008-5472.can-12-1068.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Arzumanyan A, Sambandam V, Clayton MM, Choi SS, Xie G, Diehl AM, et al. Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. Cancer Res. 2012;72(22):5912–20. doi: 10.1158/0008-5472.can-12-2329.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Pereira Tde A, Witek RP, Syn WK, Choi SS, Bradrick S, Karaca GF, et al. Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. Lab Investig. 2010;90(12):1690–703. doi: 10.1038/labinvest.2010.147.CrossRefPubMedGoogle Scholar
  105. 105.
    Philips GM, Chan IS, Swiderska M, Schroder VT, Guy C, Karaca GF, et al. Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer. PLoS One. 2011;6(9):e23943. doi: 10.1371/journal.pone.0023943.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Jeng KS, Jeng CJ, Jeng WJ, Sheen IS, Chang CF, Hsiau HI, et al. Sonic hedgehog pathway inhibitor mitigates mouse hepatocellular carcinoma. Am J Surg. 2015;210(3):554–60. doi: 10.1016/j.amjsurg.2015.03.001.CrossRefPubMedGoogle Scholar
  107. 107.
    Oishi N, Yamashita T, Kaneko S. Molecular biology of liver cancer stem cells. Liver Cancer. 2014;3(2):71–84. doi: 10.1159/000343863.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Yamashita T, Budhu A, Forgues M, Wang XW. Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res. 2007;67(22):10831–9. doi: 10.1158/0008-5472.CAN-07-0908.CrossRefPubMedGoogle Scholar
  109. 109.
    Ji J, Yamashita T, Budhu A, Forgues M, Jia HL, Li C, et al. Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology. 2009;50(2):472–80. doi: 10.1002/hep.22989.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Su R, Nan H, Guo H, Ruan Z, Jiang L, Song Y, et al. Associations of components of PTEN/AKT/mTOR pathway with cancer stem cell markers and prognostic value of these biomarkers in hepatocellular carcinoma. Hepatol Res. 2016;46(13):1380–91. doi: 10.1111/hepr.12687.CrossRefPubMedGoogle Scholar
  111. 111.
    Firtina Karagonlar Z, Koc D, Sahin E, Avci ST, Yilmaz M, Atabey N, et al. Effect of adipocyte-secreted factors on EpCAM+/CD133+ hepatic stem cell population. Biochem Biophys Res Commun. 2016;474(3):482–90. doi: 10.1016/j.bbrc.2016.04.137.CrossRefPubMedGoogle Scholar
  112. 112.
    Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66(24):11851–8. doi: 10.1158/0008-5472.CAN-06-1377.CrossRefPubMedGoogle Scholar
  113. 113.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al., Group SIS. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90. doi: 10.1056/NEJMoa0708857.CrossRefGoogle Scholar
  114. 114.
    Firtina Karagonlar Z, Koc D, Iscan E, Erdal E, Atabey N. Elevated hepatocyte growth factor expression as an autocrine c-Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells. Cancer Sci. 2016;107(4):407–16. doi: 10.1111/cas.12891.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Jiang X, Feng K, Zhang Y, Li Z, Zhou F, Dou H, Wang T (2015) Sorafenib and DE605, a novel c-Met inhibitor, synergistically suppress hepatocellular carcinoma. Oncotarget 6 (14):12340-12356. doi:  10.18632/oncotarget.3656.
  116. 116.
    Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14(1):55–63. doi: 10.1016/S1470-2045(12)70490-4.CrossRefPubMedGoogle Scholar
  117. 117.
    Finn RS. Emerging targeted strategies in advanced hepatocellular carcinoma. Semin Liver Dis. 2013;33(Suppl 1):S11–9. doi: 10.1055/s-0033-1333632.CrossRefPubMedGoogle Scholar
  118. 118.
    Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008;26(18):2992–8. doi: 10.1200/JCO.2007.15.9947.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Zhu AX, Blaszkowsky LS, Ryan DP, Clark JW, Muzikansky A, Horgan K, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24(12):1898–903. doi: 10.1200/JCO.2005.04.9130.CrossRefPubMedGoogle Scholar
  120. 120.
    Yamaguchi H, Chang SS, Hsu JL, Hung MC. Signaling cross-talk in the resistance to HER family receptor targeted therapy. Oncogene. 2014;33(9):1073–81. doi: 10.1038/onc.2013.74.CrossRefPubMedGoogle Scholar
  121. 121.
    Jo M, Stolz DB, Esplen JE, Dorko K, Michalopoulos GK, Strom SC. Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J Biol Chem. 2000;275(12):8806–11.CrossRefGoogle Scholar
  122. 122.
    Reznik TE, Sang Y, Ma Y, Abounader R, Rosen EM, Xia S, et al. Transcription-dependent epidermal growth factor receptor activation by hepatocyte growth factor. Mol Cancer Res. 2008;6(1):139–50. doi: 10.1158/1541-7786.MCR-07-0236.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Nath D, Williamson NJ, Jarvis R, Murphy G. Shedding of c-Met is regulated by crosstalk between a G-protein coupled receptor and the EGF receptor and is mediated by a TIMP-3 sensitive metalloproteinase. J Cell Sci. 2001;114(Pt 6):1213–20.PubMedGoogle Scholar
  124. 124.
    Korhan P, Erdal E, Kandemis E, Cokakli M, Nart D, Yilmaz F, et al. Reciprocal activating crosstalk between c-Met and caveolin 1 promotes invasive phenotype in hepatocellular carcinoma. PLoS One. 2014;9(8):e105278. doi: 10.1371/journal.pone.0105278.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Bozkaya G, Korhan P, Cokakli M, Erdal E, Sagol O, Karademir S, et al. Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis. Mol Cancer. 2012;11:64. doi: 10.1186/1476-4598-11-64.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Vlodavsky I, Korner G, Ishai-Michaeli R, Bashkin P, Bar-Shavit R, Fuks Z. Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis. Cancer Metastasis rev. 1990;9(3):203–26.CrossRefGoogle Scholar
  127. 127.
    Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 2003;125(1):89–97.CrossRefGoogle Scholar
  128. 128.
    Suzuki M, Sugimoto K, Tanaka J, Tameda M, Inagaki Y, Kusagawa S, et al. Up-regulation of glypican-3 in human hepatocellular carcinoma. Anticancer Res. 2010;30(12):5055–61.PubMedGoogle Scholar
  129. 129.
    Kemp LE, Mulloy B, Gherardi E. Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors. Biochem Soc Trans. 2006;34(Pt 3):414–7. doi: 10.1042/BST0340414.CrossRefPubMedGoogle Scholar
  130. 130.
    Ozen E, Gozukizil A, Erdal E, Uren A, Bottaro DP, Atabey N. Heparin inhibits hepatocyte growth factor induced motility and invasion of hepatocellular carcinoma cells through early growth response protein 1. PLoS One. 2012;7(8):e42717. doi: 10.1371/journal.pone.0042717.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Iscan E, Gunes A, Korhan P, Yilmaz Y, Erdal E, Atabey N. The regulatory role of heparin on c-Met signaling in hepatocellular carcinoma cells. J Cell Commun Signal. 2016; doi: 10.1007/s12079-016-0368-0.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Yeliz Yılmaz
    • 1
    • 2
  • Ayşim Güneş
    • 1
  • Hande Topel
    • 1
    • 2
  • Neşe Atabey
    • 1
    • 3
    Email author
  1. 1.Izmir International Biomedicine & Genome Institute (iBG-izmir)Dokuz Eylul UniversityIzmirTurkey
  2. 2.Department of Medical Biology and Genetics, Institute of Health SciencesDokuz Eylul UniversityIzmirTurkey
  3. 3.Department of Medical Biology, Faculty of MedicineDokuz Eylul UniversityIzmirTurkey

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