Skip to main content

Advertisement

SpringerLink
Log in

Signaling Pathways as Potential Therapeutic Targets in Hepatocarcinogenesis

  • Review Article
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  3. Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology. 2011;140(5):1410–26. doi:10.1053/j.gastro.2011.03.006.

    Article  CAS  PubMed  Google Scholar 

  4. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118–27. doi:10.1056/NEJMra1001683.

    Article  CAS  PubMed  Google Scholar 

  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.

  6. Bruix J. Liver cancer: still a long way to go. Hepatology. 2011;54(1):1–2. doi:10.1002/hep.24468.

    Article  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  12. Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Med. 1998;49:407–24. doi:10.1146/annurev.med.49.1.407.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  20. Ferrara N. The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS. 2005;94:209–31.

    Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  55. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2(5):e1600200. doi:10.1126/sciadv.1600200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mertens C, Darnell JE Jr. SnapShot: JAK-STAT signaling. Cell. 2007;131(3):612. doi:10.1016/j.cell.2007.10.033.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  79. Muller PA, Vousden KH. p53 mutations in cancer. Nat Cell Biol. 2013;15(1):2–8. doi:10.1038/ncb2641.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  83. Ilagan MX, Kopan R. SnapShot: notch signaling pathway. Cell. 2007;128(6):1246. doi:10.1016/j.cell.2007.03.011.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  95. Chen MH, Wilson CW, Chuang PT. SnapShot: hedgehog signaling pathway. Cell. 2007;130(2):386. doi:10.1016/j.cell.2007.07.017.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey

    Yeliz Yılmaz, Ayşim Güneş, Hande Topel & Neşe Atabey

  2. Department of Medical Biology and Genetics, Institute of Health Sciences, Dokuz Eylul University, 35340, Izmir, Turkey

    Yeliz Yılmaz & Hande Topel

  3. Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, 35340, Izmir, Turkey

    Neşe Atabey

Authors
  1. Yeliz Yılmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayşim Güneş
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hande Topel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Neşe Atabey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Neşe Atabey.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yılmaz, Y., Güneş, A., Topel, H. et al. Signaling Pathways as Potential Therapeutic Targets in Hepatocarcinogenesis. J Gastrointest Canc 48, 225–237 (2017). https://doi.org/10.1007/s12029-017-9958-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-017-9958-1

Keywords

Search

Navigation