Molecular mechanism of hepatocellular carcinoma

Abstract

Development of hepatocellular carcinoma (HCC) is very complex and occurs through a multistep biological process of malignant transformation of normal hepatocytes in which various factors, including genetic and epigenetic alterations, regulation of oxidative stress, inflammation, and immunity are involved. To date, numerous studies have described the molecular pathogenesis of HCC, but the precise molecular mechanisms of HCC development remain unclear. Emerging single-cell transcriptome analysis technology is a powerful tool for defining sub-populations within heterogeneous bulk tumor tissue and allows molecular characterization of each cell. This breakthrough method can unveil the molecular mechanisms of HCC. In this article, I discuss recent advances in the molecular pathogenesis of HCC through this newly emerging concept of single-cell analysis.

Keywords

Hepatocellular carcinoma / molecular mechanism / pathogenesis / characterization

References

[1] Yang JD.Epidemiology and management of hepatocellular carcinoma.Infect Dis Clin North Am2010;24:899-919, viii PMCID:PMC3949429

[2] Venook AP,Furuse J.The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective.Oncologist2010;15 Suppl 4:5-13

[3] Sanyal AJ,Lencioni R.The etiology of hepatocellular carcinoma and consequences for treatment.Oncologist2010;15 Suppl 4:14-22

[4] Welzel TM,Zeuzem S,Davila JA.Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database.Hepatology2011;54:463-71 PMCID:PMC4141525

[5] Liu Y,Marsh GM.Population attributable risk of aflatoxin-related liver cancer: systematic review and meta-analysis.Eur J Cancer2012;48:2125-36 PMCID:PMC3374897

[6] Ferber MJ,Yu C,McGee A,Nagorney DM,Burgart LJ,Bruix J,Cheung TH,Wong YF,Roberts LR.Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers.Oncogene2003;22:3813-20

[7] Zhang X.Key role of hepatitis B virus mutation in chronic hepatitis B development to hepatocellular carcinoma.World J Hepatol2015;7:1282-6 PMCID:PMC4438503

[8] Sung WK,Li S,Liu X,Lee NP,Ariyaratne PN,Mulawadi FH,Liu AM,Fan ST,Gong Z,Lin Z,Zhang Q,Chou WC,Hao K,Zhang C,Buser C,Kan Z,Mao M,Wang J.Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma.Nat Genet2012;44:765-9

[9] Nault JC,Pilati C,Bioulac-Sage P,Laurent A,Balabaud C.High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions.Nat Commun2013;4:2218 PMCID:PMC3731665

[10] Bell RJ,Kreig A,Fouse SD,Choi S,He D,Wiencke JK,Chang SM,Myong S,Costello JF.Cancer.The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science2015;348:1036-9 PMCID:PMC4456397

[11] Zhang T,You X,Du Y,Shan C,Wang Y,Ye L.Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells.Hepatology2012;56:2051-9

[12] Maguire HF,Siddiqui A.HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions.Science1991;252:842-4

[13] Chan C,Chow PK,Ooi LL.Altered binding site selection of p53 transcription cassettes by hepatitis B virus X protein.Mol Cell Biol2013;33:485-97 PMCID:PMC3554210

[14] Yun C,Jin YH,Lee MO,Lee JH.NF-kappaB activation by hepatitis B virus X (HBx) protein shifts the cellular fate toward survival.Cancer Lett2002;184:97-104

[15] Klein NP.Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras.Mol Cell Biol1997;17:6427-36

[16] Benn J.Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade.Proc Natl Acad Sci U S A1994;91:10350-4 PMCID:PMC45017

[17] Lee YI,Do SI.The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade.J Biol Chem2001;276:16969-77

[18] Cha MY,Park YM.Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells.Hepatology2004;39:1683-93

[19] Tian Y,Song J,Ni B.Hepatitis B virus X protein-induced aberrant epigenetic modifications contributing to human hepatocellular carcinoma pathogenesis.Mol Cell Biol2013;33:2810-6 PMCID:PMC3719687

[20] Zhu YZ,Fan J,Li H,Zhu HG.Hepatitis B virus X protein induces hypermethylation of p16(INK4A) promoter via DNA methyltransferases in the early stage of HBV-associated hepatocarcinogenesis.J Viral Hepat2010;17:98-107

[21] Kong G,Zhang S,Ye L.Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model.PLoS One2011;6:e19518 PMCID:PMC3088678

[22] Rusyn I.Mechanisms of HCV-induced liver cancer: what did we learn from in vitro and animal studies?.Cancer Lett2014;345:210-5 PMCID:PMC3844040

[23] Lerat H,Pawlotsky JM.Animal models in the study of hepatitis C virus-associated liver pathologies.Expert Rev Gastroenterol Hepatol2011;5:341-52

[24] Lindenbach BD,Syder AJ,Tellinghuisen TL,Maruyama T,Burton DR,Rice CM.Complete replication of hepatitis C virus in cell culture.Science2005;309:623-6

[25] Lohmann V,Koch J,Theilmann L.Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line.Science1999;285:110-3

[26] Tacke RS,Nguyen V,Hahn YS.Extracellular hepatitis C virus core protein activates STAT3 in human monocytes/macrophages/dendritic cells via an IL-6 autocrine pathway.J Biol Chem2011;286:10847-55 PMCID:PMC3060535

[27] Zhu Z,Gopalakrishna K,Luxon BA.Hepatitis C virus core protein enhances Telomerase activity in Huh7 cells.J Med Virol2010;82:239-48

[28] He Q,Chen Z,Xiao Z,Li B,Zheng H.Cell transformation and proteome alteration in QSG7701 cells transfected with hepatitis C virus non-structural protein 3.Acta Biochim Biophys Sin (Shanghai).2007;39:751-62

[29] Kwun HJ,Ahn JY,Jang KL.p53-dependent transcriptional repression of p21(waf1) by hepatitis C virus NS3.J Gen Virol2001;82:2235-41

[30] Yu GY,Li CY,Grivennikov S,Wu MS,Tsai Y,Karin M.Hepatic expression of HCV RNA-dependent RNA polymerase triggers innate immune signaling and cytokine production.Mol Cell2012;48:313-21 PMCID:PMC3483424

[31] Korenaga M,Li Y,Chan T,Weinman SA.Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production.J Biol Chem2005;280:37481-8

[32] Munakata T,Liang Y,Lemon SM.Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase.Proc Natl Acad Sci U S A2005;102:18159-64 PMCID:PMC1307512

[33] Choi SH.Modulation of the transforming growth factor-beta signal transduction pathway by hepatitis C virus nonstructural 5A protein.J Biol Chem2006;281:7468-78

[34] Tsai WC,Hsu CS,Chen SJ,Huang Y,Lee CH,Hsu MT,Huang HD,Hsiao M.MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis.J Clin Invest2012;122:2884-97 PMCID:PMC3408747

[35] Smeenk R,Aarden L.Influence of pH on the detection of low- and high-avidity anti-dsDNA.J Immunol Methods1982;55:361-73

[36] Abbas Z,Abbas S.Hepatitis D and hepatocellular carcinoma.World J Hepatol2015;7:777-86 PMCID:PMC4404383

[37] Schwartz JM.Prevalence and natural history of alcoholic liver disease.Clin Liver Dis2012;16:659-66

[38] Neuman MG,Maor Y,Melzer E,Seitz HK,Mell H,Cohen LB,Osna NA,Thompson KJ,Bautista A,French SW.Alcoholic liver disease: clinical and translational research.Exp Mol Pathol2015;99:596-610

[39] Plemenitas A,Porcelli S,Rus Makovec M,Dolzan V.Genetic variability in CYP2E1 and catalase gene among currently and formerly alcohol-dependent male subjects.Alcohol Alcohol2015;50:140-5

[40] Polonikov AV,Solodilova MA.CYP2E1 gene promoter polymorphism -1293G>C increases the risk of essential hypertension in men with alcohol abuse.Bull Exp Biol Med2013;155:734-7

[41] Liu W,Dai L.Cytochrome P450 2E1 gene polymorphism and alcohol drinking on the risk of hepatocellular carcinoma: a meta-analysis.Mol Biol Rep2014;41:7645-50

[42] Schulze K,Letouze E,Calderaro J,Couchy G,Shinde J,Calatayud AL,Pelletier L,Laurent A,Mazzaferro V,Villanueva A,Bioulac-Sage P,Llovet JM.Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.Nat Genet2015;47:505-11 PMCID:PMC4587544

[43] Sebastian C,Haigis MC.From sirtuin biology to human diseases: an update.J Biol Chem2012;287:42444-52 PMCID:PMC3522245

[44] You M,Ajmo JM.Involvement of mammalian sirtuin 1 in the action of ethanol in the liver.Am J Physiol Gastrointest Liver Physiol2008;294:G892-8

[45] Stunkel W,Tan YC,Wang X,Ni B,Wood J.Function of the SIRT1 protein deacetylase in cancer.Biotechnol J2007;2:1360-8

[46] Luo J,Imai S,Su F,Guarente L.Negative control of p53 by Sir2alpha promotes cell survival under stress.Cell2001;107:137-48

[47] Yeung F,Ramsey CS,Jones DR,Mayo MW.Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.EMBO J2004;23:2369-80 PMCID:PMC423286

[48] Jang KY,Lehwald N,Bellovin DI,Moon WS,Sylvester KG.SIRT1 and c-Myc promote liver tumor cell survival and predict poor survival of human hepatocellular carcinomas.PLoS One2012;7:e45119 PMCID:PMC3443243

[49] Mercer KE,Ronis MJ.Alcohol consumption, Wnt/beta-catenin signaling, and hepatocarcinogenesis.Adv Exp Med Biol2015;815:185-95 PMCID:PMC5600155

[50] Lindenmeyer CC.The natural history of nonalcoholic fatty liver disease-an evolving view.Clin Liver Dis2018;22:11-21

[51] Agosti P,Mazzocca A.Emerging metabolic risk factors in hepatocellular carcinoma and their influence on the liver microenvironment.Biochim Biophys Acta2018;1864:607-17

[52] Wong RJ,Cheung R,Harrison SA,Ahmed A.Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.Gastroenterology2015;148:547-55

[53] Wu J.Utilization of animal models to investigate nonalcoholic steatohepatitis-associated hepatocellular carcinoma.Oncotarget2016;7:42762-76

[54] Ding J.Epigenetic regulation of hepatic tumor-initiating cells.Front Biosci (Landmark Ed).2015;20:946-63

[55] Stickel F.Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications.Gut2010;59:1303-7

[56] Park EJ,Yu GY,Ali SR,Osterreicher CH,Karin M.Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.Cell2010;140:197-208 PMCID:PMC2836922

[57] Yoshimoto S,Atarashi K,Sato S,Iwakura Y,Morita H,Honda K,Hara E.Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.Nature2013;499:97-101

[58] Streba LA,Rogoveanu I.Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: an open question.World J Gastroenterol2015;21:4103-10 PMCID:PMC4394070

[59] Hardy T,Anstee QM.Nonalcoholic fatty liver disease: pathogenesis and disease spectrum.Annu Rev Pathol2016;11:451-96

[60] Wang Z,Snyder M.RNA-Seq: a revolutionary tool for transcriptomics.Nat Rev Genet2009;10:57-63 PMCID:PMC2949280

[61] Miyamoto DT,Wittner BS,Zhu H,Desai R,Brannigan BW,Arora KS,Dahl DM,Smith MR,Wu CL,Ramaswamy S,Toner M,Haber DA.RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance.Science2015;349:1351-6 PMCID:PMC4872391

[62] Xu S,Wu Y,Zhang JB,Ye H,Wei S,Wu WJ,Shi R,Huang XF,Chen J.Circulating tumor DNA identified by targeted sequencing in advanced-stage non-small cell lung cancer patients.Cancer Lett2016;370:324-31

[63] Liang DH,Liu ZB,Patel TA,Rodriguez AA.Cell-free DNA as a molecular tool for monitoring disease progression and response to therapy in breast cancer patients.Breast Cancer Res Treat2016;155:139-49

[64] Huang Q,Liu H,Mo F,Li L,Tian T,Shen F,Chen ZN.RNA-Seq analyses generate comprehensive transcriptomic landscape and reveal complex transcript patterns in hepatocellular carcinoma.PLoS One2011;6:e26168 PMCID:PMC3197143

[65] Marusyk A,Polyak K.Intra-tumour heterogeneity: a looking glass for cancer?.Nat Rev Cancer2012;12:323-34

[66] Hou Y,Cao C,Hu B,Wu X,Tang F,Peng J.Single-cell triple omics sequencing reveals genetic, epigenetic, and transcriptomic heterogeneity in hepatocellular carcinomas.Cell Res2016;26:304-19 PMCID:PMC4783472

[67] Zheng H,Hernandez MO,Livak F,Dang H,Davis JL,Mehta M,Shetty J,Budhu A.Single cell analysis reveals cancer stem cell heterogeneity in hepatocellular carcinoma.Hepatology2018;68:127-40

[68] Hurez V,Svatek RS.Considerations for successful cancer immunotherapy in aged hosts.Exp Gerontol2018;107:27-36

[69] Curiel TJ.Regulatory T cells and treatment of cancer.Curr Opin Immunol2008;20:241-6 PMCID:PMC3319305

[70] Wherry EJ.T cell exhaustion.Nat Immunol2011;12:492-9

[71] Kasper HU,Stippel DL,Gillessen A.Liver tumor infiltrating lymphocytes: comparison of hepatocellular and cholangiolar carcinoma.World J Gastroenterol2009;15:5053-7 PMCID:PMC2768884

[72] Zheng C,Yoo JK,Zhang Y,Kang B,Huang JY,Liu Z,Hu X,Peng J.Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing.Cell2017;169:1342-56.e16