Molecular diagnosis and therapy of hepatocellular carcinoma: achievements and challenges

Xiao-Dong Zhang , Man Zhao

Hepatoma Research ›› 2019, Vol. 5 : 14

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Hepatoma Research ›› 2019, Vol. 5:14 DOI: 10.20517/2394-5079.2018.117
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Molecular diagnosis and therapy of hepatocellular carcinoma: achievements and challenges

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Abstract

Hepatocellular carcinoma (HCC) is often associated with pre-existing chronic liver pathologies of different origin infections of hepatitis B virus (HBV) and hepatitis C virus. Clinically, the diagnosis and therapy for HCC are very important for the prognosis of patients. However, current methods for HCC diagnosis and therapy have no an optimal accuracy due to the tumor heterogeneity and the frequent late diagnosis. This review summarizes the new advances in molecular diagnosis and therapy of HCC, based on the recent novel biomarkers and new therapeutic strategies for HCC, including alpha-fetoprotein-L3, glypican-3, heat shock protein 90, dickkopf WNT signaling pathway inhibitor 1, paraoxonase 1, highly up-regulated in liver cancer. Moreover, epigenetic regulation, signal pathway, cellular and molecular targets for the immunotherapy, tumor microenviroment and genome sequencing analysis may serve as the molecular expression signatures in clinical practice. For promising new treatment strategy of HCC, targeting molecular therapy based on the restoration of tumor suppressor genes lost and inhibition of oncogenic genes is attractive. The new clinical trials for other molecular-targeted agents, including pembrolizumab, nivolumab, tivantinib, lenvatinib, cabozantinib, and ramucirumab, are ongoing in clinic. Interestingly, anti-HBV drugs display an amazing therapy for HBV-related HCC. In future, the global determination of more biomarkers may provide new insights into the diagnosis of HCC. More importantly, the diagnostic markers should be used to trace patient’s follow-up disease progression, guiding doctors to judge and prescribe drugs for status of an illness, prognosis and other processes.

Keywords

Molecular diagnosis / therapy / hepatocellular carcinoma / hepatitis B virus / hepatitis C virus

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Xiao-Dong Zhang, Man Zhao. Molecular diagnosis and therapy of hepatocellular carcinoma: achievements and challenges. Hepatoma Research, 2019, 5: 14 DOI:10.20517/2394-5079.2018.117

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References

[1]

Petrick JL,Altekruse SF,Rosenberg PS.Future of hepatocellular carcinoma incidence in the United States forecast through 2030..J Clin Oncol2016;34:1787-94 PMCID:PMC4966339

[2]

Xu Y,Dai C.High serum microRNA-122 level is independently associated with higher overall survival rate in hepatocellular carcinoma patients..Tumor Biol2015;36:4773-6

[3]

Hamid AS,Zhang Y.Aflatoxin B1-induced hepatocellular carcinoma in developing countries: geographical distribution, mechanism of action and prevention..Oncol Lett2013;5:1087-92 PMCID:PMC3629261

[4]

Mak LY,Chinchilla-Lopez P,LoConte NK.Global epidemiology, prevention, and management of hepatocellular carcinoma..Am Soc Clin Oncol Educ Book2018;38:262-79

[5]

Crocetti L,Cioni R.Loco-regional treatment of HCC: current status..Clin Radiol2017;72:626-35

[6]

Juarez-Hernandez E,Chavez-Tapia NC,Barbero Becerra V.Biomarkers in hepatocellular carcinoma: an overview..Expert Rev Gastroenterol Hepatol2017;11:549-58

[7]

Borel F,Jansen PL.Diagnostic and therapeutic potential of miRNA signatures in patients with hepatocellular carcinoma..J Hepatol2012;56:1371-83

[8]

Manini MA,Fornari F,Biolato M.Clinical and economical impact of 2010 AASLD guidelines for the diagnosis of hepatocellular carcinoma..J Hepatol2014;60:995-1001

[9]

Mitchell PS,Kroh EM,Wyman SK.Circulating microRNAs as stable blood-based markers for cancer detection..Proc Nati Acadof Sci U S A2008;105:10513-8 PMCID:PMC2492472

[10]

Bianchi F,Marzi M,Dall’olio V.A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancer..EMBO Mol Med2011;3:495-503 PMCID:PMC3377091

[11]

Ji J,Budhu A,Jia HL.Let-7g targets collagen type I alpha2 and inhibits cell migration in hepatocellular carcinoma..J Hepatol2010;52:690-7 PMCID:PMC2862772

[12]

Zhang J,Yang T,Li A.microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity..Br J Cancer2010;103:1215-20 PMCID:PMC2967065

[13]

Ji J,Budhu A,Forgues M.MicroRNA expression, survival, and response to interferon in liver cancer..N Engl J Med2009;361:1437-47 PMCID:PMC2786938

[14]

Xiong Y,Yun JP,Zhang Y.Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma..Hepatology2010;51:836-45

[15]

Li D,Lin L,Li N.MicroRNA-99a inhibits hepatocellular carcinoma growth and correlates with prognosis of patients with hepatocellular carcinoma..J Biol Chem2011;286:36677-85 PMCID:PMC3196113

[16]

Zheng F,Cai MY,Liu TH.The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2..Gut2012;61:278-89

[17]

Wong CC,Tung EK,Lee JM.The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2..Gastroenterology2011;140:322-31

[18]

Jia YS,Zhuang QS,Yang ZH.Tumorigenicity of cancer stem-like cells derived from hepatocarcinoma is regulated by microRNA-145..Oncol Rep2012;27:1865-72

[19]

Wang C,Song W,Sun A.Underexpressed microRNA-199b-5p targets hypoxia-inducible factor-1alpha in hepatocellular carcinoma and predicts prognosis of hepatocellular carcinoma patients..J Gastroenterol Hepatol2011;26:1630-7

[20]

Li QJ,Yang F,Zheng H.MicroRNA-10b promotes migration and invasion through CADM1 in human hepatocellular carcinoma cells..Tumor Biol2012;33:1455-65

[21]

Chen L,Yuan W.miR-17-5p as a novel prognostic marker for hepatocellular carcinoma..J Invest Surg2012;25:156-61

[22]

Karakatsanis A,Gazouli M,Polymeneas G.Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance..Mole Carcinog2013;52:297-303

[23]

Liu S,Shi J,Yu X.MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma..J Hepatol2012;56:389-96

[24]

Han ZB,Fan JW,Tang HM.Up-regulation of microRNA-155 promotes cancer cell invasion and predicts poor survival of hepatocellular carcinoma following liver transplantation..J Cancer Res Clin Oncol2012;138:153-61

[25]

Wang J,Shen J,Yang L.MicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma..BMC Cancer2012;12:227 PMCID:PMC3492170

[26]

Wong QWL,Chan AW,To KF.MiR-222 overexpression confers cell migratory advantages in hepatocellular carcinoma through enhancing AKT signaling..Clin Cancer Res2010;16:867-75

[27]

Toffanin S,Lachenmayer A,Cabellos L.MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a..Gastroenterology2011;140:1618-28 PMCID:PMC3680790

[28]

Xie Y,Butt AM,Tian Z.Expression profiling of serum microRNA-101 in HBV-associated chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma..Cancer Biol Ther2014;15:1248-55 PMCID:PMC4128867

[29]

Li L,Wang J,Gao Q.Serum miR-18a: a potential marker for hepatitis B virus-related hepatocellular carcinoma screening..Dig Dis Sci2012;57:2910-6

[30]

Su ZX,Rong ZH,Wu YG.Upregulation of microRNA-25 associates with prognosis in hepatocellular carcinoma..Diagn Pathol2014;9:47 PMCID:PMC4016611

[31]

Han ZB,Fan JW,Tang HM.Up-regulation of microRNA-155 promotes cancer cell invasion and predicts poor survival of hepatocellular carcinoma following liver transplantation..J Cancer Res Clin Oncol2012;138:153-61

[32]

Yamamoto Y,Tanaka M,Kanai Y.MicroRNA-500 as a potential diagnostic marker for hepatocellular carcinoma..Biomarkers2009;14:529-38

[33]

Li LM,Zhou ZX,Liu FY.Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma..Cancer Res2010;70:9798-807

[34]

Tsai MC,Wan Y,Wang JK.Long noncoding RNA as modular scaffold of histone modification complexes..Science2010;329:689-93 PMCID:PMC2967777

[35]

Rinn JL,Wang JK,Xu X.Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs..Cell2007;129:1311-23 PMCID:PMC2084369

[36]

Li Y,Shi H,Li L.HBXIP and LSD1 scaffolded by lncRNA Hotair mediate transcriptional activation by c-Myc..Cancer Res2016;76:293-304

[37]

Yang Z,Wu LM,Xie HY.Overexpression of long non-coding RNA Hotair predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation..Ann Surg Oncol2011;18:1243-50

[38]

Xie H,Zhou DQ.Plasma HULC as a promising novel biomarker for the detection of hepatocellular carcinoma..Biomed Res Int2013;2013:136106 PMCID:PMC3674644

[39]

Cui M,Wang Y,Song T.Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway..Cancer Res2015;75:846-57

[40]

Du Y,You X,Zhang T.Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18..J Biol Chem2012;287:26302-11 PMCID:PMC3406714

[41]

Wang Y,Zhao M,Li J.The long noncoding RNA HULC promotes liver cancer by increasing the expression of the HMGA2 oncogene via sequestration of the microRNA-186..J Biol Chem2017;292:15395-407 PMCID:PMC5602398

[42]

Zhao J,Gray SG.Long noncoding RNAs in liver cancer: what we know in 2014..Expert Opin Ther Targets2014;18:1207-18

[43]

Hernandez-Vargas H,Le Calvez-Kelm F,McKay-Chopin S.Hepatocellular carcinoma displays distinct DNA methylation signatures with potential as clinical predictors..PLoS One2010;5:e9749 PMCID:PMC2840036

[44]

Nagashio R,Ojima H,Kondo Y.Carcinogenetic risk estimation based on quantification of DNA methylation levels in liver tissue at the precancerous stage..Int J Cancer2011;129:1170-9

[45]

Shen J,Zhang YJ,Wu HC.Genome-wide DNA methylation profiles in hepatocellular carcinoma..Hepatology2012;55:1799-808 PMCID:PMC3330167

[46]

He C,Zhang J,Ye H.High expression of trimethylated histone H3 lysine 4 is associated with poor prognosis in hepatocellular carcinoma..Hum Pathol2012;43:1425-35

[47]

Cai MY,Rao HL,Li M.High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts worse prognosis in patients..Mol Med2011;17:12-20 PMCID:PMC3022987

[48]

Zhang ZQ,Wang N,Liu LN.Serum microRNA 143 and microRNA 215 as potential biomarkers for the diagnosis of chronic hepatitis and hepatocellular carcinoma..Diagn Pathol2014;9:1-7 PMCID:PMC4226970

[49]

Taketa K,Sekiya C,Koji T.A collaborative study for the evaluation of lectin-reactive alpha-fetoproteins in early detection of hepatocellular carcinoma..Cancer Res1993;53:5419-23

[50]

Caviglia GP,Petrini E,Rizzetto M.Highly sensitive alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxyprothrombin for hepatocellular carcinoma detection..Hepatol Res2016;46:E130-5

[51]

Capurro M,Sherman M,Shi W.Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma..Gastroenterology2003;125:89-97

[52]

Hippo Y,Watanabe A,Yamamoto S.Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma..Cancer Res2004;64:2418-23

[53]

Fu Y,Huang D,Liu L.Plasma heat shock protein 90alpha as a biomarker for the diagnosis of liver cancer: an official, large-scale, and multicenter clinical trial..EBioMedicine2017;24:56-63 PMCID:PMC5652007

[54]

Shen Q,Yang XR,Zhao W.Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study..Lancet Oncol2012;13:817-26

[55]

Abdel Wahab AHA,Emam AA,Abd Elmageed ZY.Identification of circulating protein biomarkers in patients with hepatocellular carcinoma concomitantly infected with chronic hepatitis C virus..Biomarkers2017;22:621-8

[56]

Zhang S,Zhang Q,Liu Y.Serum fucosylated paraoxonase 1 as a potential glycobiomarker for clinical diagnosis of early hepatocellular carcinoma using ELISA Index..Glycoconj J2015;32:119-25

[57]

Zhang W,Wu M,Zhang M.PRMT5 restricts hepatitis B virus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation..Hepatology2017;66:398-415

[58]

Ganem D.Hepatitis B virus infection - natural history and clinical consequences..N Engl J Med2004;351:351

[59]

Cheng HY,Chuang YH,Jan MC.Circulating programmed death-1 as a marker for sustained high hepatitis B viral load and risk of hepatocellular carcinoma..PLos One2014;9:e95870 PMCID:PMC4245192

[60]

Durantel D.New antiviral targets for innovative treatment concepts for hepatitis B virus and hepatitis delta virus..J Hepatol2016;64:S117-S131

[61]

Zhang X,Ye L.Effects of hepatitis B virus X protein on the development of liver cancer..J Lab Clin Med2006;147:58-66

[62]

Zhang XD,Ye LH.Hepatitis B virus X protein accelerates the development of hepatoma..Cancer Biol Med2014;11:182-90 PMCID:PMC4197427

[63]

Gao Y,Yang G,Liu Y.Hepatitis B virus X protein-elevated MSL2 modulates hepatitis B virus covalently closed circular DNA by inducing degradation of APOBEC3B to enhance hepatocarcinogenesis..Hepatology2017;66:1413-29

[64]

Zhang H,Zhang S,Li N.Anti-Hepatitis B virus X protein in sera is one of the markers of development of liver cirrhosis and liver cancer mediated by HBV..J Biomed Biotechnol2009;2009:289068 PMCID:PMC2738860

[65]

Zhang S,Zhao M,Bu Y.Anti-HBV drugs suppress the growth of HBV-related hepatoma cells via down-regulation of hepatitis B virus X protein..Cancer Lett2017;392:94-104

[66]

Xie QK,Pan T,Mu LW.Programmed death ligand 1 as an indicator of pre-existing adaptive immune responses in human hepatocellular carcinoma..Oncoimmunology2016;5:e1181252 PMCID:PMC5006919

[67]

Sun J,Tian D,Shen Z.Icotinib inhibits the proliferation of hepatocellular carcinoma cells in vitro and in vivo dependently on EGFR activation and PDL1 expression..Onco Targets Ther2018;11:8227-37 PMCID:PMC6254541

[68]

Mocan T,Craciun R,Leucuta DC.Programmed cell death protein-1 (PD-1)/programmed death-ligand-1 (PD-L1) axis in hepatocellular carcinoma: prognostic and therapeutic perspectives..Clin Transl Oncol2018;

[69]

El-Khoueiry AB,Yau T,Kudo M.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial..Lancet2017;389:2492-502

[70]

Raoul JL,Finn RS,Reig M.Systemic therapy for intermediate and advanced hepatocellular carcinoma: sorafenib and beyond..Cancer Treat Rev2018;68:16-24

[71]

Best J,Lohmann G,Dechene A.Tivantinib for the treatment of hepatocellular carcinoma..Expert Opin Pharmacother2017;18:727-33

[72]

Ikeda K,Kawazoe S,Ikeda M.Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma..Journal of Gastroenterology2017;52:512-9 PMCID:PMC5357473

[73]

Bruix J,Merle P,Huang YH.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial..Lancet2017;389:56-66

[74]

Finn RS,Granito A,Bodoky G.Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial..J Hepatol2018;69:353-8

[75]

Abou-Alfa GK,Cheng AL,Rimassa L.Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase 3 CELESTIAL trial..J Clin Oncol2018;36:

[76]

Khoja L,Kang SP,Joshua AM.Pembrolizumab..J Immunother Cancer2015;3:36 PMCID:PMC4539882

[77]

Zhu AX,Yen CJ,Poon RTP.Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): Analysis of patients with elevated alpha-fetoprotein (AFP) from the randomized phase III REACH study..J Clin Oncol2015;33:

[78]

Yakes FM,Tan J,Shi Y.Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth..Mol Cancer Ther2011;10:2298-308

[79]

Zhu AX,Ryoo BY,Poon R.Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial..Lancet Oncol2015;16:859-70

[80]

Kudo M.Positioning of a molecular-targeted agent, sorafenib, in the treatment algorithm for hepatocellular carcinoma and implication of many complete remission cases in Japan..Oncology.2010;78 Suppl 1:154-66

[81]

Lu L,Pei Y,Qin L,Jia H.Down-regulation of SDF1-α expression in tumor microenvironment is associated with aspirin-mediated suppression of the pro-metastasis effect of sorafenib in hepatocellular carcinoma..Acta Biochim Biophys Sin2015;47:988-96

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