Skip to main content
SpringerLink
Log in

Crosstalk of Molecular Signaling in Hepatocellular Carcinoma

  • Chapter
  • First Online:
Book cover Liver Diseases

Abstract

Hepatocellular carcinoma (HCC) is a primary liver malignancy with high morbidity and mortality worldwide. The development of HCC is a complex multistep process associated with an accumulation of molecular changes that run through the steps of initiation, promotion and progression. Research conducted over the past decades has lead to the identification of several important molecular pathways, including ERK/MAPK pathway, PI3K/Akt/mTOR pathway, WNT/β-catenin pathway, TGF-β pathway, JAK/STAT pathway, and MDM2-p53 pathway that are frequently dysregulated in HCC. Here we explore their relative importance and crosstalk which will provide insights into the molecular biology and targeted therapy implicated in HCC.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.

    Article  CAS  PubMed  Google Scholar 

  2. Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD. Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol. 2008;14(27):4300–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Liu PH, Hsu CY, Hsia CY, Lee YH, Huang YH, Chiou YY, et al. Surgical resection versus radiofrequency ablation for single hepatocellular carcinoma </= 2 cm in a propensity score model. Ann Surg. 2016;263(3):538–45.

    Article  PubMed  Google Scholar 

  4. Kao WY, Chao Y, Chang CC, Li CP, Su CW, Huo TI, et al. Prognosis of early-stage hepatocellular carcinoma: the clinical implications of substages of Barcelona clinic liver cancer system based on a cohort of 1265 patients. Medicine. 2015;94(43):e1929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang Y, Luo Q, Li Y, Deng S, Wei S, Li X. Radiofrequency ablation versus hepatic resection for small hepatocellular carcinomas: a meta-analysis of randomized and nonrandomized controlled trials. PLoS One. 2014;9(1):e84484.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Peng ZW, Lin XJ, Zhang YJ, Liang HH, Guo RP, Shi M, et al. Radiofrequency ablation versus hepatic resection for the treatment of hepatocellular carcinomas 2 cm or smaller: a retrospective comparative study. Radiology. 2012;262(3):1022–33.

    Article  PubMed  Google Scholar 

  7. Colagrande S, Inghilesi AL, Aburas S, Taliani GG, Nardi C, Marra F. Challenges of advanced hepatocellular carcinoma. World J Gastroenterol. 2016;22(34):7645–59.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.

    Article  CAS  PubMed  Google Scholar 

  9. Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015;12(8):436.

    Article  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36(6):320–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Logue JS, Morrison DK. Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy. Genes Dev. 2012;26(7):641–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hubbard SR, Miller WT. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol. 2007;19(2):117–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19(49):5548–57.

    Article  CAS  PubMed  Google Scholar 

  16. Hubbard SR. Structural analysis of receptor tyrosine kinases. Prog Biophys Mol Biol. 1999;71(3–4):343–58.

    Article  CAS  PubMed  Google Scholar 

  17. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990;61(2):203–12.

    Article  CAS  PubMed  Google Scholar 

  18. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Muntane J, De la Rosa AJ, Docobo F, Garcia-Carbonero R, Padillo FJ. Targeting tyrosine kinase receptors in hepatocellular carcinoma. Curr Cancer Drug Targets. 2013;13(3):300–12.

    Article  CAS  PubMed  Google Scholar 

  20. Avila MA, Berasain C, Sangro B, Prieto J. New therapies for hepatocellular carcinoma. Oncogene. 2006;25(27):3866–84.

    Article  CAS  PubMed  Google Scholar 

  21. Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 2007;27(1):55–76.

    Article  CAS  PubMed  Google Scholar 

  22. Huynh H, Nguyen TT, Chow KH, Tan PH, Soo KC, Tran E. Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterol. 2003;3:19.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006;130(4):1117–28.

    Article  CAS  PubMed  Google Scholar 

  24. Newell P, Toffanin S, Villanueva A, Chiang DY, Minguez B, Cabellos L, et al. Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol. 2009;51(4):725–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schlessinger J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell. 2002;110(6):669–72.

    Article  CAS  PubMed  Google Scholar 

  26. Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, et al. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992;70(3):431–42.

    Article  CAS  PubMed  Google Scholar 

  27. Zheng Y, Zhang C, Croucher DR, Soliman MA, St-Denis N, Pasculescu A, et al. Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Nature. 2013;499(7457):166–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zarich N, Oliva JL, Martinez N, Jorge R, Ballester A, Gutierrez-Eisman S, et al. Grb2 is a negative modulator of the intrinsic Ras-GEF activity of hSos1. Mol Biol Cell. 2006;17(8):3591–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schulze K, Nault JC, Villanueva A. Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J Hepatol. 2016;65(5):1031–42.

    Article  CAS  PubMed  Google Scholar 

  30. Li X, Xu W, Kang W, Wong SH, Wang M, Zhou Y, et al. Genomic analysis of liver cancer unveils novel driver genes and distinct prognostic features. Theranostics. 2018;8(6):1740–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Matallanas D, Birtwistle M, Romano D, Zebisch A, Rauch J, von Kriegsheim A, et al. Raf family kinases: old dogs have learned new tricks. Genes Cancer. 2011;2(3):232–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22(2):153–83.

    CAS  PubMed  Google Scholar 

  33. Chen RH, Sarnecki C, Blenis J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol. 1992;12(3):915–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xing J, Ginty DD, Greenberg ME. Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science. 1996;273(5277):959–63.

    Article  CAS  PubMed  Google Scholar 

  35. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 2000;14(19):2501–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang Y, Kwok-Shing Ng P, Kucherlapati M, Chen F, Liu Y, Tsang YH, et al. A pan-cancer proteogenomic atlas of PI3K/AKT/mTOR pathway alterations. Cancer Cell. 2017;31(6):820–32. e3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Czech MP. PIP2 and PIP3: complex roles at the cell surface. Cell. 2000;100(6):603–6.

    Article  CAS  PubMed  Google Scholar 

  38. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A. 1999;96(8):4240–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Peyrou M, Bourgoin L, Foti M. PTEN in liver diseases and cancer. World J Gastroenterol. 2010;16(37):4627–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest. 2004;113(12):1774–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu D, Wong CC, Fu L, Chen H, Zhao L, Li C, et al. Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target. Sci Transl Med. 2018;10(437):pii: eaap9840.

    Article  CAS  Google Scholar 

  43. Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology. 2008;135(6):1972–83. 83.e1–11

    Article  CAS  PubMed  Google Scholar 

  44. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471–84.

    Article  CAS  PubMed  Google Scholar 

  45. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25(6):903–15.

    Article  CAS  PubMed  Google Scholar 

  46. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):873–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4(9):648–57.

    Article  CAS  PubMed  Google Scholar 

  48. Kodaki T, Woscholski R, Hallberg B, Rodriguez-Viciana P, Downward J, Parker PJ. The activation of phosphatidylinositol 3-kinase by Ras. Curr Biol. 1994;4(9):798–806.

    Article  CAS  PubMed  Google Scholar 

  49. Gupta S, Ramjaun AR, Haiko P, Wang Y, Warne PH, Nicke B, et al. Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell. 2007;129(5):957–68.

    Article  CAS  PubMed  Google Scholar 

  50. Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature. 2001;410(6832):1111–6.

    Article  CAS  PubMed  Google Scholar 

  51. Wang C, Cigliano A, Delogu S, Armbruster J, Dombrowski F, Evert M, et al. Functional crosstalk between AKT/mTOR and Ras/MAPK pathways in hepatocarcinogenesis: implications for the treatment of human liver cancer. Cell Cycle. 2013;12(13):1999–2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell. 2005;121(2):179–93.

    Article  CAS  PubMed  Google Scholar 

  53. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci U S A. 2004;101(37):13489–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Carriere A, Cargnello M, Julien LA, Gao H, Bonneil E, Thibault P, et al. Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr Biol. 2008;18(17):1269–77.

    Article  CAS  PubMed  Google Scholar 

  55. Carriere A, Romeo Y, Acosta-Jaquez HA, Moreau J, Bonneil E, Thibault P, et al. ERK1/2 phosphorylate Raptor to promote Ras-dependent activation of mTOR complex 1 (mTORC1). J Biol Chem. 2011;286(1):567–77.

    Article  CAS  PubMed  Google Scholar 

  56. Hoeflich KP, O’Brien C, Boyd Z, Cavet G, Guerrero S, Jung K, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res. 2009;15(14):4649–64.

    Article  CAS  PubMed  Google Scholar 

  57. Yu CF, Liu ZX, Cantley LG. ERK negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase. J Biol Chem. 2002;277(22):19382–8.

    Article  CAS  PubMed  Google Scholar 

  58. Lehr S, Kotzka J, Avci H, Sickmann A, Meyer HE, Herkner A, et al. Identification of major ERK-related phosphorylation sites in Gab1. Biochemistry. 2004;43(38):12133–40.

    Article  CAS  PubMed  Google Scholar 

  59. Moelling K, Schad K, Bosse M, Zimmermann S, Schweneker M. Regulation of Raf-Akt Cross-talk. J Biol Chem. 2002;277(34):31099–106.

    Article  CAS  PubMed  Google Scholar 

  60. Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science. 1999;286(5445):1741–4.

    Article  CAS  PubMed  Google Scholar 

  61. Jaumot M, Hancock JF. Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions. Oncogene. 2001;20(30):3949–58.

    Article  CAS  PubMed  Google Scholar 

  62. Xin B, Yamamoto M, Fujii K, Ooshio T, Chen X, Okada Y, et al. Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways. Oncogene. 2017;36(36):5087–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, et al. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell. 2005;19(2):159–70.

    Article  CAS  PubMed  Google Scholar 

  64. Tsai WB, Aiba I, Long Y, Lin HK, Feun L, Savaraj N, et al. Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells. Cancer Res. 2012;72(10):2622–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gregory MA, Qi Y, Hann SR. Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J Biol Chem. 2003;278(51):51606–12.

    Article  CAS  PubMed  Google Scholar 

  66. Zhu J, Blenis J, Yuan J. Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc Natl Acad Sci U S A. 2008;105(18):6584–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011;1813(11):1978–86.

    Article  CAS  PubMed  Google Scholar 

  68. Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10(2):138–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis. 2008;4(2):68–75.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Huang HC, Klein PS. The Frizzled family: receptors for multiple signal transduction pathways. Genome Biol. 2004;5(7):234.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Li VS, Ng SS, Boersema PJ, Low TY, Karthaus WR, Gerlach JP, et al. Wnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex. Cell. 2012;149(6):1245–56.

    Article  CAS  PubMed  Google Scholar 

  72. Kishida S, Yamamoto H, Ikeda S, Kishida M, Sakamoto I, Koyama S, et al. Axin, a negative regulator of the wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of beta-catenin. J Biol Chem. 1998;273(18):10823–6.

    Article  CAS  PubMed  Google Scholar 

  73. Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108(6):837–47.

    Article  CAS  PubMed  Google Scholar 

  74. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997;16(13):3797–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors. Oncogene. 2006;25(27):3778–86.

    Article  CAS  PubMed  Google Scholar 

  77. Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene. 2006;25(27):3787–800.

    Article  CAS  PubMed  Google Scholar 

  78. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13(1):11–26.

    Article  CAS  PubMed  Google Scholar 

  79. Schulze K, Imbeaud S, Letouze E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47(5):505–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46(12):1267–73.

    Article  CAS  PubMed  Google Scholar 

  81. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell. 2006;126(5):955–68.

    Article  CAS  PubMed  Google Scholar 

  82. Castilho RM, Squarize CH, Chodosh LA, Williams BO, Gutkind JS. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell. 2009;5(3):279–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008;412(2):179–90.

    Article  CAS  PubMed  Google Scholar 

  84. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378(6559):785–9.

    Article  CAS  PubMed  Google Scholar 

  85. Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, et al. Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem. 2007;282(15):11221–9.

    Article  CAS  PubMed  Google Scholar 

  86. Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69(18):7385–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Steinway SN, Zanudo JG, Ding W, Rountree CB, Feith DJ, Loughran TP Jr, et al. Network modeling of TGFbeta signaling in hepatocellular carcinoma epithelial-to-mesenchymal transition reveals joint sonic hedgehog and Wnt pathway activation. Cancer Res. 2014;74(21):5963–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Jian H, Shen X, Liu I, Semenov M, He X, Wang XF. Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev. 2006;20(6):666–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Goumans MJ, Mummery C. Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. Int J Dev Biol. 2000;44(3):253–65.

    CAS  PubMed  Google Scholar 

  90. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113(6):685–700.

    Article  CAS  PubMed  Google Scholar 

  91. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, et al. Smad6 inhibits signalling by the TGF-beta superfamily. Nature. 1997;389(6651):622–6.

    Article  CAS  PubMed  Google Scholar 

  92. Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature. 1997;389(6651):631–5.

    Article  CAS  PubMed  Google Scholar 

  93. Xu Z, Shen MX, Ma DZ, Wang LY, Zha XL. TGF-beta1-promoted epithelial-to-mesenchymal transformation and cell adhesion contribute to TGF-beta1-enhanced cell migration in SMMC-7721 cells. Cell Res. 2003;13(5):343–50.

    Article  PubMed  Google Scholar 

  94. van Malenstein H, Dekervel J, Verslype C, Van Cutsem E, Windmolders P, Nevens F, et al. Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth. Cancer Lett. 2013;329(1):74–83.

    Article  PubMed  CAS  Google Scholar 

  95. Dazert E, Colombi M, Boldanova T, Moes S, Adametz D, Quagliata L, et al. Quantitative proteomics and phosphoproteomics on serial tumor biopsies from a sorafenib-treated HCC patient. Proc Natl Acad Sci U S A. 2016;113(5):1381–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425(6958):577–84.

    Article  CAS  PubMed  Google Scholar 

  97. Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000;275(47):36803–10.

    Article  CAS  PubMed  Google Scholar 

  98. Vinals F, Pouyssegur J. Transforming growth factor beta1 (TGF-beta1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-alpha signaling. Mol Cell Biol. 2001;21(21):7218–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chen RH, Su YH, Chuang RL, Chang TY. Suppression of transforming growth factor-beta-induced apoptosis through a phosphatidylinositol 3-kinase/Akt-dependent pathway. Oncogene. 1998;17(15):1959–68.

    Article  CAS  PubMed  Google Scholar 

  100. Yue J, Mulder KM. Activation of the mitogen-activated protein kinase pathway by transforming growth factor-beta. Methods Mol Biol. 2000;142:125–31.

    CAS  PubMed  Google Scholar 

  101. Mulder KM, Morris SL. Activation of p21ras by transforming growth factor beta in epithelial cells. J Biol Chem. 1992;267(8):5029–31.

    CAS  PubMed  Google Scholar 

  102. Fransvea E, Mazzocca A, Santamato A, Azzariti A, Antonaci S, Giannelli G. Kinase activation profile associated with TGF-beta-dependent migration of HCC cells: a preclinical study. Cancer Chemother Pharmacol. 2011;68(1):79–86.

    Article  CAS  PubMed  Google Scholar 

  103. Jatiani SS, Baker SJ, Silverman LR, Reddy EP. Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes Cancer. 2010;1(10):979–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Aaronson DS, Horvath CM. A road map for those who don't know JAK-STAT. Science. 2002;296(5573):1653–5.

    Article  CAS  PubMed  Google Scholar 

  105. Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol. 2003;3(11):900–11.

    Article  CAS  PubMed  Google Scholar 

  106. Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62.

    Article  CAS  PubMed  Google Scholar 

  107. Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet. 2001;28(1):29–35.

    CAS  PubMed  Google Scholar 

  108. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004;117(Pt 8):1281–3.

    Article  CAS  PubMed  Google Scholar 

  109. Andl CD, Mizushima T, Oyama K, Bowser M, Nakagawa H, Rustgi AK. EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes. Am J Physiol Gastrointest Liver Physiol. 2004;287(6):G1227–37.

    Article  CAS  PubMed  Google Scholar 

  110. Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science. 1996;274(5289):948–53.

    Article  CAS  PubMed  Google Scholar 

  111. Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;6(12):909–23.

    Article  CAS  PubMed  Google Scholar 

  112. Barak Y, Gottlieb E, Juven-Gershon T, Oren M. Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. Genes Dev. 1994;8(15):1739–49.

    Article  CAS  PubMed  Google Scholar 

  113. Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25(3):304–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Willis A, Jung EJ, Wakefield T, Chen X. Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes. Oncogene. 2004;23(13):2330–8.

    Article  CAS  PubMed  Google Scholar 

  115. Persons DL, Yazlovitskaya EM, Pelling JC. Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin. J Biol Chem. 2000;275(46):35778–85.

    Article  CAS  PubMed  Google Scholar 

  116. She QB, Chen N, Dong Z. ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. J Biol Chem. 2000;275(27):20444–9.

    Article  CAS  PubMed  Google Scholar 

  117. Yeh PY, Chuang SE, Yeh KH, Song YC, Chang LL, Cheng AL. Phosphorylation of p53 on Thr55 by ERK2 is necessary for doxorubicin-induced p53 activation and cell death. Oncogene. 2004;23(20):3580–8.

    Article  CAS  PubMed  Google Scholar 

  118. Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, et al. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 2006;10(6):459–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ferbeyre G, de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ, et al. Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol. 2002;22(10):3497–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M. Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene. 2002;21(8):1299–303.

    Article  CAS  PubMed  Google Scholar 

  121. Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem. 2002;277(24):21843–50.

    Article  CAS  PubMed  Google Scholar 

  122. Nault JC, Zucman-Rossi J. TERT promoter mutations in primary liver tumors. Clin Res Hepatol Gastroenterol. 2016;40(1):9–14.

    Article  CAS  PubMed  Google Scholar 

  123. Satyanarayana A, Manns MP, Rudolph KL. Telomeres and telomerase: a dual role in hepatocarcinogenesis. Hepatology. 2004;40(2):276–83.

    Article  CAS  PubMed  Google Scholar 

  124. Luedde T, Schwabe RF. NF-kappaB in the liver—linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2011;8(2):108–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Karin M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol. 2009;1(5):a000141.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Xu W, Zhang X, Wu JL, Fu L, Liu K, Liu D, et al. O-GlcNAc transferase promotes fatty liver-associated liver cancer through inducing palmitic acid and activating endoplasmic reticulum stress. J Hepatol. 2017;67(2):310–20.

    Article  CAS  PubMed  Google Scholar 

  127. 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.

    Article  CAS  PubMed  Google Scholar 

  128. Huang S, He J, Zhang X, Bian Y, Yang L, Xie G, et al. Activation of the hedgehog pathway in human hepatocellular carcinomas. Carcinogenesis. 2006;27(7):1334–40.

    Article  CAS  PubMed  Google Scholar 

  129. Della Corte CM, Viscardi G, Papaccio F, Esposito G, Martini G, Ciardiello D, et al. Implication of the Hedgehog pathway in hepatocellular carcinoma. World J Gastroenterol. 2017;23(24):4330–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Blivet-Van Eggelpoel MJ, Chettouh H, Fartoux L, Aoudjehane L, Barbu V, Rey C, et al. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol. 2012;57(1):108–15.

    Article  CAS  PubMed  Google Scholar 

  132. Ito Y, Takeda T, Sakon M, Tsujimoto M, Higashiyama S, Noda K, et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer. 2001;84(10):1377–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ezzoukhry Z, Louandre C, Trecherel E, Godin C, Chauffert B, Dupont S, et al. EGFR activation is a potential determinant of primary resistance of hepatocellular carcinoma cells to sorafenib. Int J Cancer. 2012;131(12):2961–9.

    Article  CAS  PubMed  Google Scholar 

  134. Gedaly R, Angulo P, Hundley J, Daily MF, Chen C, Koch A, et al. PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Anticancer Res. 2010;30(12):4951–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Thng CH, et al. Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Cell Mol Med. 2009;13(8B):2673–83.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Chen KF, Chen HL, Tai WT, Feng WC, Hsu CH, Chen PJ, et al. Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J Pharmacol Exp Ther. 2011;337(1):155–61.

    Article  CAS  PubMed  Google Scholar 

  137. Chen KF, Tai WT, Hsu CY, Huang JW, Liu CY, Chen PJ, et al. Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity. Eur J Med Chem. 2012;55:220–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Sha Tin, Hong Kong, China

    Huarong Chen & Jun Yu

Authors
  1. Huarong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun Yu .

Editor information

Editors and Affiliations

  1. Faculty of Medicine, “Titu Maiorescu” University, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania

    Florentina Radu-Ionita

  2. New Jersey Medical School, Rutgers University New Jersey Medical School, Newark, NJ, USA

    Nikolaos T. Pyrsopoulos

  3. Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania

    Mariana Jinga

  4. Faculty of Medicine, “Titu Maiorescu” University, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania

    Ion C. Tintoiu

  5. Medical Radiation Sciences, Curtin University, Perth, WA, Australia

    Zhonghua Sun

  6. “Prof. C.C. Iliescu” Emergency Institute for Cardiovascular Diseases, Bucharest, Romania

    Ecaterina Bontas

Self Study

Self Study

1.1 Questions

  1. (a)

    The process by which molecular signals are transmitted from a cell’s exterior to its interior as a series of molecular events is called ________.

  2. (b)

    Instances in which one or more components of one signal transduction pathway affects another are called ________.

1.2 Answers

  1. (a)

    Signal transduction

  2. (b)

    Crosstalk

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Chen, H., Yu, J. (2020). Crosstalk of Molecular Signaling in Hepatocellular Carcinoma. In: Radu-Ionita, F., Pyrsopoulos, N., Jinga, M., Tintoiu, I., Sun, Z., Bontas, E. (eds) Liver Diseases. Springer, Cham. https://doi.org/10.1007/978-3-030-24432-3_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-24432-3_8

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-24431-6

  • Online ISBN: 978-3-030-24432-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation