Skip to main content

Advertisement

Log in

Cellular and molecular mechanisms of hepatocellular carcinoma: an update

  • Review Article
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor that accounts for ~80 % of all liver cancer cases worldwide. It is a multifactorial disease caused by a variety of risk factors and often develops in the background of underlying cirrhosis. A number of cellular phenomena, such as tumor microenvironment, inflammation, oxidative stress, and hypoxia act in concert with various molecular events to facilitate tumor initiation, progression, and metastasis. The emergence of microRNAs and molecular-targeted therapies adds a new dimension in our efforts to combat this deadly disease. Intense research in this multitude of areas has led to significant progress in our understanding of cellular processes and molecular mechanisms that occur during multistage events that lead to hepatocarcinogenesis. In this review, we discuss the current knowledge of HCC, focusing mainly on advances that have occurred during the past 5 years and on the development of novel therapeutics for liver cancer.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abel S, De Kock M, van Schalkwyk DJ, Swanevelder S, Kew MC, Gelderblom WC (2009) Altered lipid profile, oxidative status and hepatitis B virus interactions in human hepatocellular carcinoma. Prostaglandins Leukot Essent Fatty Acids 81(5–6):391–399

    Article  PubMed  CAS  Google Scholar 

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988

    Article  PubMed  CAS  Google Scholar 

  • Anson M, Crain-Denoyelle AM, Baud V, Chereau F, Gougelet A, Terris B, Yamagoe S, Colnot S, Viguier M, Perret C, Couty JP (2012) Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J Clin Invest 122(2):586–599

    Article  PubMed  CAS  Google Scholar 

  • Aravalli RN, Cressman EN (2009) Molecular signaling in hepatocelluar carcinoma. Cancer Chemother Rev 4:157–164

    Google Scholar 

  • Aravalli RN, Steer CJ, Cressman EN (2008) Molecular mechanisms of hepatocellular carcinoma. Hepatology 48(6):1049–1053

    Article  CAS  Google Scholar 

  • Bader AG (2012) miR-34 - a microRNA replacement therapy is headed to the clinic. Front Genet 3:120

    PubMed  Google Scholar 

  • Bai S, Nasser MW, Wang B, Hsu SH, Datta J, Kutay H, Yadav A, Nuovo G, Kumar P, Ghoshal K (2009) MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib. J Biol Chem 284(46):32015–32027

    Article  PubMed  CAS  Google Scholar 

  • Bala S, Marcos M, Szabo G (2009) Emerging role of microRNAs in liver diseases. World J Gastroenterol 15(45):5633–5640

    Article  PubMed  CAS  Google Scholar 

  • Barajas M, Mazzolini G, Genové G, Bilbao R, Narvaiza I, Schmitz V, Sangro B, Melero I, Qian C, Prieto J (2001) Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12. Hepatology 33(1):52–61

    Article  PubMed  CAS  Google Scholar 

  • Benetti A, Berenzi A, Gambarotti M, Garrafa E, Gelati M, Dessy E, Portolani N, Piardi T, Giulini SM, Caruso A, Invernici G, Parati EA, Nicosia R, Alessandri G (2008) Transforming growth factor-β1 and CD105 promote the migration of hepatocellular carcinoma–derived endothelium. Cancer Res 68(20):8626–8634

    Article  PubMed  CAS  Google Scholar 

  • Bergamini C, Sgarra C, Trerotoli P, Lupo L, Azzariti A, Antonaci S, Giannelli G (2007) Laminin-5 stimulates hepatocellular carcinoma growth through a different function of α6β4 and α3β1 integrins. Hepatology 46(6):1801–1809

    Article  PubMed  CAS  Google Scholar 

  • Bochud PY, Bibert S, Kutalik Z, Patin E, Guergnon J, Nalpas B, Goossens N, Kuske L, Müllhaupt B, Gerlach T, Heim MH, Moradpour D, Cerny A, Malinverni R, Regenass S, Dollenmaier G, Hirsch H, Martinetti G, Gorgiewski M, Bourlière M, Poynard T, Theodorou I, Abel L, Pol S, Dufour JF, Negro F (2012) IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes. Hepatology 55(2):384–394

    Article  PubMed  CAS  Google Scholar 

  • Bortolami M, Venturi C, Giacomelli L, Scalerta R, Bacchetti S, Marino F, Floreani A, Lise M, Naccarato R, Farinati F (2002) Cytokine, infiltrating macrophage and T cell-mediated response to development of primary and secondary human liver cancer. Dig Liver Dis 34(11):794–801

    Article  PubMed  CAS  Google Scholar 

  • Braconi C, Henry JC, Kogure T, Schmittgen T, Patel T (2011) The role of microRNAs in human liver cancers. Semin Oncol 38(6):752–763

    Article  PubMed  CAS  Google Scholar 

  • Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, Kammula US, Chen Y, Qin LX, Tang ZY, Wang XW (2006) Prediction of venous metastases, recurrence and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 10(2):99–111

    Article  PubMed  CAS  Google Scholar 

  • Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, Zanetti KA, Ye QH, Qin LX, Croce CM, Tang ZY, Wang XW (2008) Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 47(3):897–907

    Article  PubMed  CAS  Google Scholar 

  • Burchard J, Zhang C, Liu AM, Poon RT, Lee NP, Wong KF, Sham PC, Lam BY, Ferguson MD, Tokiwa G, Smith R, Leeson B, Beard R, Lamb JR, Lim L, Mao M, Dai H, Luk JM (2010) microRNA-122 as a regulator of mitochondrial metabolic gene network in hepatocellular carcinoma. Mol Syst Biol 6:402

    Article  PubMed  CAS  Google Scholar 

  • Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6(11):857–866

    Article  PubMed  CAS  Google Scholar 

  • Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 101(9):2999–3004

    Article  PubMed  CAS  Google Scholar 

  • Calvisi D, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, Factor VM, Thorgeirsson SS (2006) Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130(4):1117–1128

    Article  PubMed  CAS  Google Scholar 

  • Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS, Haran AC, Odell MM, Bauer RL, Ren HP, Haugen HS, Yeh MM, Fausto N (2005) Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci USA 102(9):3389–3394

    Article  PubMed  CAS  Google Scholar 

  • Carr BI, Wang Z, Wang M, Cavallini A, D’Alessandro R, Refolo MG (2011) c-Met-Akt pathway-mediated enhancement of inhibitory c-Raf phosphorylation is involved in vitamin K1 and sorafenib synergy on HCC growth inhibition. Cancer Biol Ther 12(6):531–538

    Article  PubMed  CAS  Google Scholar 

  • Castoldi M, Vujic Spasic M, Altamura S, Elmén J, Lindow M, Kiss J, Stolte J, Sparla R, D’Alessandro LA, Klingmüller U, Fleming RE, Longerich T, Gröne HJ, Benes V, Kauppinen S, Hentze MW, Muckenthaler MU (2011) The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice. J Clin Invest 121(4):1386–1396

    Article  PubMed  CAS  Google Scholar 

  • Chen XM (2009) MicroRNA signatures in liver diseases. World J Gastroenterol 15(14):1665–1672

    Article  PubMed  CAS  Google Scholar 

  • Chen L, Chan TH, Yuan YF, Hu L, Huang J, Ma S, Wang J, Dong SS, Tang KH, Xie D, Li Y, Guan XY (2010a) CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients. J Clin Invest 120(4):1178–1191

    Article  PubMed  CAS  Google Scholar 

  • Chen PJ, Furuse J, Han KH, Hsu C, Lim HY, Moon H, Qin S, Ye SL, Yeoh EM, Yeo W (2010b) Issues and controversies of hepatocellular carcinoma-targeted therapy clinical trials in Asia: experts’ opinion. Liver Int 30(10):1427–1438

    Article  PubMed  Google Scholar 

  • Chen KJ, Zhou L, Xie HY, Ahmed TE, Feng XW, Zheng SS (2012) Intratumoral regulatory T cells alone or in combination with cytotoxic T cells predict prognosis of hepatocellular carcinoma after resection. Med Oncol 29(3):1817–1826

    Google Scholar 

  • Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, Kellum JM, Min H, Luketic VA, Sanyal AJ (2008) Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. Hepatology 48(6):1810–1820

    Article  PubMed  CAS  Google Scholar 

  • Chew V, Chen J, Lee D, Loh E, Lee J, Lim KH, Weber A, Slankamenac K, Poon RT, Yang H, Ooi LL, Toh HC, Heikenwalder M, Ng IO, Nardin A, Abastado JP (2012) Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut 61(3):427–438

    Article  PubMed  CAS  Google Scholar 

  • Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, Nakauchi H, Taniguchi H (2006) Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 44(1):240–251

    Article  PubMed  CAS  Google Scholar 

  • Chuma M, Hige S, Nakanishi M, Ogawa K, Natsuizaka M, Yamamoto Y, Asaka M (2008) 8-Hydroxy-2’-deoxy-guanosine is a risk factor for development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol 23(9):1431–1436

    Article  PubMed  Google Scholar 

  • Cogliati B, Aloia TP, Bosch RV, Alves VA, Hernandez-Blazquez FJ, Dagli ML (2010) Identification of hepatic stem/progenitor cells in canine hepatocellular and cholangiocellular carcinoma. Vet Comp Oncol 8(2):112–121

    Article  PubMed  CAS  Google Scholar 

  • Colnot S, Decaens T, Niwa-Kawakita M, Godard C, Hamard G, Kahn A, Giovannini M, Perret C (2005) Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci USA 101(49):17216–17221

    Article  CAS  Google Scholar 

  • Connolly E, Melegari M, Landgraf P, Tchaikovskaya T, Tennant BC, Slagle BL, Rogler LE, Zavolan M, Tuschl T, Rogler CE (2008) Elevated expression of the miR-17-92 polycistron and miR-21 in hepadnavirus-associated hepatocellular carcinoma contributes to the malignant phenotype. Am J Pathol 173(3):856–864

    Article  PubMed  CAS  Google Scholar 

  • Copple BL (2010) Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia inducible factor- and transforming growth factor-β-dependent Mechanisms. Liver Int 30(5):669–682

    Article  PubMed  CAS  Google Scholar 

  • Croker BA, Kiu H, Nicholson SE (2008) SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol 19(4):412–422

    Google Scholar 

  • Datta J, Kutay H, Nasser MW, Nuovo GJ, Wang B, Majumder S, Liu CG, Volinia S, Croce CM, Schmittgen TD, Ghoshal K, Jacob ST (2008) Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res 68(13):5049–5058

    Article  PubMed  CAS  Google Scholar 

  • Davies C, Tournier C (2012) Exploring the function of the JNK (c-Jun N-terminal kinase) signalling pathway in physiological and pathological processes to design novel therapeutic strategies. Biochem Soc Transact 40(1):85–89

    Article  CAS  Google Scholar 

  • de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C (1998) Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 95(15):8847–8851

    Article  Google Scholar 

  • Del Barco Barrantes I, Nebreda AR (2012) Roles of p38 MAPKs in invasion and metastasis. Biochem Soc Transact 40(1):79–84

    Article  CAS  Google Scholar 

  • Ding W, You H, Dang H, LeBlanc F, Galicia V, Lu SC, Stiles B, Rountree CB (2010) Epithelial-to-mesenchymal transition of murine liver tumor cells promotes invasion. Hepatology 52(3):945–953

    Article  PubMed  CAS  Google Scholar 

  • Du H, Yang W, Chen L, Shen B, Peng C, Li H, Ann DK, Yen Y, Qiu W (2012) Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma. Int J Oncol 40(6):2049–2057

    PubMed  CAS  Google Scholar 

  • Ebert MS, Sharp PA (2012) Roles for microRNAs in conferring robustness to biological processes. Cell 149(3):515–524

    Article  PubMed  CAS  Google Scholar 

  • El-Serag HB (2012) Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142(6):1264–1273

    Article  PubMed  Google Scholar 

  • El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576

    Article  PubMed  CAS  Google Scholar 

  • Elsharkawy AM, Mann DA (2007) Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 46(2):590–597

    Article  PubMed  CAS  Google Scholar 

  • Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP (2006) miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 3(2):89–98

    Article  CAS  Google Scholar 

  • Fallot G, Neuveut C, Buendia MA (2012) Diverse roles of hepatitis B virus in liver cancer. Curr Opin Virol 2(4):467–473

    Google Scholar 

  • Fan CG, Wang CM, Tian C, Wang Y, Li L, Sun WS, Li RF, Liu YG (2011) miR-122 inhibits viral replication and cell proliferation in hepatitis B virus-related hepatocellular carcinoma and targets NDRG3. Oncol Rep 26(5):1281–1286

    PubMed  CAS  Google Scholar 

  • Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6(9):674–687

    Article  PubMed  CAS  Google Scholar 

  • Fletcher LM, Powell LW (2003) Hemochromatosis and alcoholic liver disease. Alcohol 30(2):131–136

    Article  PubMed  CAS  Google Scholar 

  • Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, Grazi GL, Giovannini C, Croce CM, Bolondi L, Negrini M (2008) MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 27(43):5651–5661

    Article  PubMed  CAS  Google Scholar 

  • Friedman SL (2008) Mechanisms of hepatic fibrogenesis. Gastroenterology 134(6):1655–1669

    Article  PubMed  CAS  Google Scholar 

  • Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, Zhang Z, Yang H, Zhang H, Zhou C, Yao J, Jin L, Wang H, Yang Y, Fu YX, Wang FS (2007a) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132(7):2328–2339

    Article  PubMed  Google Scholar 

  • Fu Y, Fang Z, Liang Y, Zhu X, Prins P, Li Z, Wang L, Sun L, Jin J, Yang Y, Zha X (2007b) Overexpression of integrin beta1 inhibits proliferation of hepatocellular carcinoma cell SMMC-7721 through preventing Skp2-dependent degradation of p27 via PI3K pathway. J Cell Biochem 102(3):704–718

    Article  PubMed  CAS  Google Scholar 

  • Giannelli G, Fransvea E, Bergamini C, Marinosci F, Antonaci S (2003) Laminin-5 chains are expressed differentially in metastatic and nonmetastatic hepatocellular carcinoma. Clin Cancer Res 9(10 Pt 1):3684–3691

    PubMed  CAS  Google Scholar 

  • Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S (2005) Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology 129(5):1375–1383

    Article  PubMed  CAS  Google Scholar 

  • Giera S, Braeuning A, Köhle C, Bursch W, Metzger U, Buchmann A, Schwarz M (2010) Wnt/β-catenin signaling activates and determines hepatic zonal expression of glutathione S-transferases in mouse liver. Toxicol Sci 115(1):22–33

    Article  PubMed  CAS  Google Scholar 

  • Goodrich DW (2006) The retinoblastoma tumor-suppressor gene, the exception that proves the rule. Oncogene 25(38):5233–5243

    Article  PubMed  CAS  Google Scholar 

  • Gouas DA, Shi H, Hautefeuille AH, Ortiz-Cuaran SL, Legros PC, Szymanska KJ, Galy O, Egevad LA, Abedi-Ardekani B, Wiman KG, Hantz O, Caron de Fromentel C, Chemin IA, Hainaut PL (2010) Effects of the TP53 p.R249S mutant on proliferation and clonogenic properties in human hepatocellular carcinoma cell lines: interaction with hepatitis B virus X protein. Carcinogenesis 31(8):1475–1482

    Article  PubMed  CAS  Google Scholar 

  • Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu CG, Calin GA, Giovannini C, Ferrazzi E, Grazi GL, Croce CM, Bolondi L, Negrini M (2007) Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res 67(13):6092–6099

    Article  PubMed  CAS  Google Scholar 

  • Gramantieri L, Fornari F, Callegari E, Sabbioni S, Lanza G, Croce CM, Bolondi L, Negrini M (2008) MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med 12(6A):2189–2204

    Article  PubMed  CAS  Google Scholar 

  • Gramantieri L, Fornari F, Ferracin M, Veronese A, Sabbioni S, Calin GA, Grazi GL, Croce CM, Bolondi L, Negrini M (2009) MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clin Cancer Res 15(16):5073–5081

    Article  PubMed  CAS  Google Scholar 

  • Grisham JW (1997) Interspecies comparison of liver carcinogenesis: implications for cancer risk assessment. Carcinogenesis 18(1):59–81

    Article  PubMed  CAS  Google Scholar 

  • Gu FM, Li QL, Gao Q, Jiang JH, Huang XY, Pan JF, Fan J, Zhou J (2011) Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3. World J Gastroenterol 17(34):3922–3932

    Article  PubMed  CAS  Google Scholar 

  • Hailfinger S, Jaworski M, Braeuning A, Buchmann A, Schwarz M (2006) Zonal gene expression in murine liver: lessons from tumors. Hepatology 43(3):407–414

    Article  PubMed  CAS  Google Scholar 

  • Hamaguchi T, Iizuka N, Tsunedomi R, Hamamoto Y, Miyamoto T, Iida M, Tokuhisa Y, Sakamoto K, Takashima M, Tamesa T, Oka M (2008) Glycolysis module activated by hypoxia-inducible factor 1α is related to the aggressive phenotype of hepatocellular carcinoma. Int J Oncol 33(4):725–731

    PubMed  CAS  Google Scholar 

  • Han YP, Zhou L, Wang J, Xiong S, Garner WL, French SW, Tsukamoto H (2004) Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen. J Biol Chem 279(6):4820–4828

    Article  PubMed  CAS  Google Scholar 

  • Harbour JW, Dean DC (2000) The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev 14(19):2393–2409

    Article  PubMed  CAS  Google Scholar 

  • Harrison DA (2012) The Jak/STAT pathway. Cold Spring Harb Perspect Biol 4(3):pii: a011205

  • Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88

    Article  PubMed  CAS  Google Scholar 

  • Henry JC, Azevedo-Pouly AC, Schmittgen TD (2011) MicroRNA replacement therapy for cancer. Pharm Res 28(12):3030–3042

    Article  PubMed  CAS  Google Scholar 

  • Heppner GH, Miller FR (1998) The cellular basis of tumor progression. Int Rev Cytol 177:1–56

    Article  PubMed  CAS  Google Scholar 

  • Hikita H, Takehara T, Shimizu S, Kodama T, Shigekawa M, Iwase K, Hosui A, Miyagi T, Tatsumi T, Ishida H, Li W, Kanto T, Hiramatsu N, Hayashi N (2010) The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. Hepatology 52(4):1310–1321

    Article  PubMed  CAS  Google Scholar 

  • Hiroishi K, Eguchi J, Baba T, Shimazaki T, Ishii S, Hiraide A, Sakaki M, Doi H, Uozumi S, Omori R, Matsumura T, Yanagawa T, Ito T, Imawari M (2010) Strong CD8+ T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma. J Gastroenterol 45(4):451–458

    Article  PubMed  CAS  Google Scholar 

  • Hossain MM, Hosono-Fukao T, Tang R, Sugaya N, van Kuppevelt TH, Jenniskens GJ, Kimata K, Rosen SD, Uchimura K (2010) Direct detection of HSulf-1 and HSulf-2 activities on extracellular heparan sulfate and their inhibition by PI-88. Glycobiology 20(2):175–186

    Article  PubMed  CAS  Google Scholar 

  • Huang S, He X (2011) The role of microRNAs in liver cancer progression. Br J Cancer 104(2):235–240

    Article  PubMed  CAS  Google Scholar 

  • Huang X, Yu C, Jin C, Kobayashi M, Bowles CA, Wang F, McKeehan WL (2006) Ectopic activity of fibroblast growth factor receptor 1 in hepatocytes accelerates hepatocarcinogenesis by driving proliferation and vascular endothelial growth factor-induced angiogenesis. Cancer Res 66(3):1481–1490

    Article  PubMed  CAS  Google Scholar 

  • Huang S, He X, Ding J, Liang L, Zhao Y, Zhang Z, Yao X, Pan Z, Zhang P, Li J, Wan D, Gu J (2008a) Upregulation of miR-23a approximately 27a approximately 24 decreases transforming growth factor-beta-induced tumor-suppressive activities in human hepatocellular carcinoma cells. Int J Cancer 123(4):972–978

    Article  PubMed  CAS  Google Scholar 

  • Huang YS, Dai Y, Yu XF, Bao SY, Yin YB, Tang M, Hu CX (2008b) Microarray analysis of microRNA expression in hepatocellular carcinoma and non-tumorous tissues without viral hepatitis. J Gastroenterol Hepatol 23(1):87–94

    Article  PubMed  CAS  Google Scholar 

  • Hussain SP, Raja K, Amstad PA, Sawyer M, Trudel LJ, Wogan GN, Hofseth LJ, Shields PG, Billiar TR, Trautwein C, Hohler T, Galle PR, Phillips DH, Markin R, Marrogi AJ, Harris CC (2000) Increased p53 mutation load in nontumorous human liver of wilson disease and hemochromatosis: oxyradical overload diseases. Proc Natl Acad Sci USA 97(23):12770–12775

    Article  PubMed  CAS  Google Scholar 

  • Iglesias BV, Centeno G, Pascuccelli H, Ward F, Peters MG, Filmus J, Puricelli L, de Kier Joffé EB (2008) Expression pattern of glypican-3 (GPC3) during human embryonic and fetal development. Histol Histopathol 23(11):1333–1340

    PubMed  CAS  Google Scholar 

  • Ishii H, Iwatsuki M, Ieta K, Ohta D, Haraguchi N, Mimori K, Mori M (2008) Cancer stem cells and chemoradiation resistance. Cancer Sci 99(10):1871–1877

    Article  PubMed  CAS  Google Scholar 

  • Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, Baba H, Mori M (2010) Epithelial–mesenchymal transition in cancer development and its clinical significance. Cancer Sci 101(2):293–299

    Article  PubMed  CAS  Google Scholar 

  • Ji J, Yamashita T, Budhu A, Forgues M, Jia HL, Li C, Deng C, Wauthier E, Reid LM, Ye QH, Qin LX, Yang W, Wang HY, Tang ZY, Croce CM, Wang XW (2009) Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology 50(2):472–480

    Article  PubMed  CAS  Google Scholar 

  • Ji J, Zhao L, Budhu A, Forgues M, Jia HL, Qin LX, Ye QH, Yu J, Shi X, Tang ZY, Wang XW (2010) Let-7 g targets collagen type I alpha2 and inhibits cell migration in hepatocellular carcinoma. J Hepatol 52(5):690–697

    Article  PubMed  CAS  Google Scholar 

  • Jiang J, Gusev Y, Aderca I, Mettler TA, Nagorney DM, Brackett DJ, Roberts LR, Schmittgen TD (2008) Association of microRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res 14(2):419–427

    Article  PubMed  CAS  Google Scholar 

  • Jopling C (2012) Liver-specific microRNA-122: biogenesis and function. RNA Biol 9(2):137–142

    Article  PubMed  CAS  Google Scholar 

  • Joshita S, Umemura T, Katsuyama Y, Ichikawa Y, Kimura T, Morita S, Kamijo A, Komatsu M, Ichijo T, Matsumoto A, Yoshizawa K, Kamijo N, Ota M, Tanaka E (2012) Association of IL28B gene polymorphism with development of hepatocellular carcinoma in Japanese patients with chronic hepatitis C virus infection. Hum Immunol 73(3):298–300

    Article  PubMed  CAS  Google Scholar 

  • Kamohara Y, Haraguchi N, Mimori K, Tanaka F, Inoue H, Mori M, Kanematsu T (2008) The search for cancer stem cells in hepatocellular carcinoma. Surgery 144(2):119–124

    Article  PubMed  Google Scholar 

  • Kikkawa Y, Sudo R, Kon J, Mizuguchi T, Nomizu M, Hirata K, Mitaka T (2008) Laminin α5 mediates ectopic adhesion of hepatocellular carcinoma through integrins and/or Lutheran/basal cell adhesion molecule. Exp Cell Res 314(14):2579–2590

    Article  PubMed  CAS  Google Scholar 

  • Kim J, Hong SJ, Park JY, Park JH, Yu YS, Park SY, Lim EK, Choi KY, Lee EK, Paik SS, Lee KG, Wang HJ, Do IG, Joh JW, Kim DS (2010) Epithelial-mesenchymal transition gene signature to predict clinical outcome of hepatocellular carcinoma. Cancer Sci 101(6):1521–1528

    Article  PubMed  CAS  Google Scholar 

  • Kitaoka S, Shiota G, Kawasaki H (2009) Serum levels of interleukin-10, interleukin-12 and soluble interleukin-2 receptor in chronic liver disease type C. Hepatogastroenterology 50(53):1569–1574

    Google Scholar 

  • Körner C, Riesner K, Krämer B, Eisenhardt M, Glässner A, Wolter F, Berg T, Müller T, Sauerbruch T, Nattermann J, Spengler U, Nischalke HD (2012) TRAIL receptor I (DR4) polymorphisms C626G and A683C are associated with an increased risk for hepatocellular carcinoma (HCC) in HCV-infected patients. BMC Cancer 12:85

    Article  PubMed  CAS  Google Scholar 

  • Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, Clark KR, Mendell JR, Mendell JT (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137(6):1005–1017

    Article  PubMed  CAS  Google Scholar 

  • Kozomara A, Griffiths-Jones S (2011) miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 39(Database issue):D152–D157

    Article  PubMed  Google Scholar 

  • Kutay H, Bai S, Datta J, Motiwala T, Pogribny I, Frankel W, Jacob ST, Ghoshal K (2006) Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem 99(3):671–678

    Article  PubMed  CAS  Google Scholar 

  • Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S, Zucman-Rossi J (2008) MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology 47(6):1955–1963

    Article  PubMed  CAS  Google Scholar 

  • Lai JP, Sandhu DS, Yu C, Han T, Moser CD, Jackson KK, Guerrero RB, Aderca I, Isomoto H, Garrity-Park MM, Zou H, Shire AM, Nagorney DM, Sanderson SO, Adjei AA, Lee JS, Thorgeirsson SS, Roberts LR (2008) Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma. Hepatology 47(4):1211–1222

    Article  PubMed  CAS  Google Scholar 

  • Lang K, Danchenko N, Gondek K, Shah S, Thompson D (2009) The burden of illness associated with hepatocellular carcinoma in the United States. J Hepatol 50(1):89–99

    Article  PubMed  Google Scholar 

  • Law PT, Wong N (2011) Emerging roles of microRNA in the intracellular signaling networks of hepatocellular carcinoma. J Gastroenterol Hepatol 26(3):437–449

    Article  PubMed  CAS  Google Scholar 

  • Lee HC, Kim M, Wands JR (2006a) Wnt/Frizzled signaling in hepatocellular carcinoma. Front Biosci 11:1901–1915

    Article  PubMed  CAS  Google Scholar 

  • Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, Wang XH, Wong YC, Guan XY, Man K, Chau KL, Fan ST (2006b) Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res 12(18):5369–5376

    Article  PubMed  CAS  Google Scholar 

  • Lee WC, Wu TJ, Chou HS, Yu MC, Hsu PY, Hsu HY, Wang CC (2012) The impact of CD4+CD25+ T cells in the tumor microenvironment of hepatocellular carcinoma. Surgery 151(2):213–222

    Article  PubMed  Google Scholar 

  • Leonardi GC, Candido S, Cervello M, Nicolosi D, Raiti F, Travali S, Spandidos DA, Libra M (2012) The tumor microenvironment in hepatocellular carcinoma (review). Int J Oncol 40(6):1733–1747

    PubMed  CAS  Google Scholar 

  • Li W, Xie L, He X, Li J, Tu K, Wei L, Wu J, Guo Y, Ma X, Zhang P, Pan Z, Hu X, Zhao Y, Xie H, Jiang G, Chen T, Wang J, Zheng S, Cheng J, Wan D, Yang S, Li Y, Gu J (2008) Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma. Int J Cancer 123(7):1616–1622

    Article  PubMed  CAS  Google Scholar 

  • Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y, Zheng X (2009) miR-34a inhibits migration and invasion by downregulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett 275(1):44–53

    Article  PubMed  CAS  Google Scholar 

  • Li YW, Qiu SJ, Fan J, Zhou J, Gao Q, Xiao YS, Xu YF (2011) Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol 54(3):497–505

    Article  PubMed  CAS  Google Scholar 

  • Liao Y, Tang ZY, Ye SL, Liu KD, Sun FX, Huang Z (2000) Modulation of apoptosis, tumorigenesity and metastatic potential with antisense H-ras oligodeoxynucleotides in a high metastatic tumor model of hepatoma: LCI-D20. Hepatogastroenterology 47(32):365–370

    PubMed  CAS  Google Scholar 

  • Libbrecht L, Roskams T (2002) Hepatic progenitor cells in human liver diseases. Semin Cell Dev Biol 13(6):389–396

    Article  PubMed  Google Scholar 

  • Lin A, Schildknecht A, Nguyen LT, Ohashi PS (2010) Dendritic cells integrate signals from the tumor microenvironment to modulate immunity and tumor growth. Immunol Lett 127(2):77–84

    Article  PubMed  CAS  Google Scholar 

  • Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C (2006) Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66(24):11851–11858

    Article  PubMed  CAS  Google Scholar 

  • Liu CJ, Lee PH, Lin DY, Wu CC, Jeng LB, Lin PW, Mok KT, Lee WC, Yeh HZ, Ho MC, Yang SS, Lee CC, Yu MC, Hu RH, Peng CY, Lai KL, Chang SS, Chen PJ (2009) Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. J Hepatol 50(5):958–968

    Article  PubMed  CAS  Google Scholar 

  • Liu L, Zhu XD, Wang WQ, Shen Y, Qin Y, Ren ZG, Sun HC, Tang ZY (2010) Activation of β-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis. Clin Cancer Res 16(10):2740–2750

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Ma Q, Zhang M, Wang X, Zhang D, Li W, Wang F, Wu E (2012) Alterations of TP53 are associated with a poor outcome for patients with hepatocellular carcinoma: Evidence from a systematic review and meta-analysis. Eur J Cancer. doi:10.1016/j.ejca.2012.03.001

  • Llovet JM, Bruix J (2008) Molecular targeted therapies in hepatocellular carcinoma. Hepatology 48(4):1312–1327

    Article  PubMed  CAS  Google Scholar 

  • Luedde T, Schwabe RF (2011) NF-κB in the liver–linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 8(2):108–118

    Article  CAS  Google Scholar 

  • Luk JM, Lam CT, Siu AF, Lam BY, Ng IO, Hu MY, Che CM, Fan ST (2006) Proteomic profiling of hepatocellular carcinoma in Chinese cohort reveals heat-shock proteins (Hsp27, Hsp70, GRP78) up-regulation and their associated prognostic values. Proteomics 6(3):1049–1057

    Article  PubMed  CAS  Google Scholar 

  • Lyons JF, Wilhelm S, Hibner B, Bollag G (2001) Discovery of a novel Raf kinase inhibitor. Endocr Relat Cancer 8(3):219–225

    Article  PubMed  CAS  Google Scholar 

  • Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, Zheng BJ, Guan XY (2007) Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132(7):2542–2556

    Article  PubMed  CAS  Google Scholar 

  • Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, Guan XY (2008a) Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res 6(7):1146–1153

    Article  PubMed  CAS  Google Scholar 

  • Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY (2008b) CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27(12):1749–1758

    Article  PubMed  CAS  Google Scholar 

  • Maeda S, Kamata H, Luo JL, Leffert H, Karin M (2005) IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121(7):977–990

    Article  PubMed  CAS  Google Scholar 

  • Maegdefrau U, Amann T, Winklmeier A, Braig S, Schubert T, Weiss TS, Schardt K, Warnecke C, Hellerbrand C, Bosserhoff AK (2009) Bone morphogenetic protein 4 is induced in hepatocellular carcinoma by hypoxia and promotes tumour progression. J Pathol 218(4):520–529

    Article  PubMed  CAS  Google Scholar 

  • Mantovani A, Sica A, Allavena P, Garlanda C, Locati M (2009) Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation. Hum Immunol 70(5):325–330

    Article  PubMed  CAS  Google Scholar 

  • Mantovani A, Germano G, Marchesi F, Locatelli M, Biswas SK (2011) Cancer-promoting tumor-associated macrophages: new vistas and open questions. Eur J Immunol 41(9):2522–2525

    Article  PubMed  CAS  Google Scholar 

  • Marabita F, Aghemo A, De Nicola S, Rumi MG, Cheroni C, Scavelli R, Crimi M, Soffredini R, Abrignani S, De Francesco R, Colombo M (2011) Genetic variation in the interleukin-28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection. Hepatology 54(4):1127–1134

    Article  PubMed  CAS  Google Scholar 

  • Marra M, Sordelli IM, Lombardi A, Lamberti M, Tarantino L, Giudice A, Stiuso P, Abbruzzese A, Sperlongano R, Accardo M, Agresti M, Caraglia M, Sperlongano P (2011) Molecular targets and oxidative stress biomarkers in hepatocellular carcinoma: an overview. J Transl Med 9:171

    Article  PubMed  CAS  Google Scholar 

  • Marrero JA, Kudo M, Bronowicki JP (2010) The challenge of prognosis and staging for hepatocellular carcinoma. Oncologist 15(suppl 4):23–33

    Article  PubMed  CAS  Google Scholar 

  • Mathai AM, Kapadia MJ, Alexander J, Kernochan LE, Swanson PE, Yeh MM (2012) Role of Foxp3-positive Tumor-infiltrating Lymphocytes in the Histologic Features and Clinical Outcomes of Hepatocellular Carcinoma. Am J Surg Pathol 36(7):980–986

    Article  PubMed  Google Scholar 

  • Matsuo N, Shiraha H, Fujikawa T, Takaoka N, Ueda N, Tanaka S, Nishina S, Nakanishi Y, Uemura M, Takaki A, Nakamura S, Kobayashi Y, Nouso K, Yagi T, Yamamoto K (2009) Twist expression promotes migration and invasion in hepatocellular carcinoma. BMC Cancer 9:240

    Article  PubMed  CAS  Google Scholar 

  • Matsushima-Nishiwaki R, Adachi S, Yoshioka T, Yasuda E, Yamagishi Y, Matsuura J, Muko M, Iwamura R, Noda T, Toyoda H, Kaneoka Y, Okano Y, Kumada T, Kozawa O (2011) Suppression by heat shock protein 20 of hepatocellular carcinoma cell proliferation via inhibition of the mitogen-activated protein kinases and AKT pathways. J Cell Biochem 112(11):3430–3439

    Article  PubMed  CAS  Google Scholar 

  • Melo SA, Esteller M (2011) Dysregulation of microRNAs in cancer: playing with fire. FEBS Lett 585(13):2087–2099

    Article  PubMed  CAS  Google Scholar 

  • Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133(2):647–658

    Article  PubMed  CAS  Google Scholar 

  • Merle P, Kim M, Herrmann M, Gupte A, Lefrançois L, Califano S, Trépo C, Tanaka S, Vitvitski L, de la Monte S, Wands JR (2005) Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma. J Hepatol 43(5):854–862

    Article  PubMed  CAS  Google Scholar 

  • Merlo LM, Pepper JW, Reid BJ, Maley CC (2006) Cancer as an evolutionary and ecological process. Nat Rev Cancer 6(12):924–935

    Article  PubMed  CAS  Google Scholar 

  • Miner JH (2008) Laminins and their roles in mammals. Microsc Res Tech 71(5):349–356

    Article  PubMed  CAS  Google Scholar 

  • Mizuno H, Ogura M, Saito Y, Sekine W, Sano R, Gotou T, Oku T, Itoh S, Katabami K, Tsuji T (2008) Changes in adhesive and migratory characteristics of hepatocellular carcinoma (HCC) cells induced by expression of α3β1 integrin. Biochim Biophys Acta 1780:564–570

    Article  PubMed  CAS  Google Scholar 

  • Morrison R, Schleicher SM, Sun Y, Niermann KJ, Kim S, Spratt DE, Chung CH, Lu B (2011) Targeting the mechanisms of resistance to chemotherapy and radiotherapy with the cancer stem cell hypothesis. J Oncol 2011:941876

    Article  PubMed  CAS  Google Scholar 

  • Movahedi K, Laoui D, Gysemans C, Baeten M, Stangé G, Van den Bossche J, Mack M, Pipeleers D, In’t Veld P, De Baetselier P, Van Ginderachter JA (2010) Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 71(14):5728–5739

    Article  Google Scholar 

  • Mueller L, Goumas FA, Affeldt M, Sandtner S, Gehling UM, Brilloff S, Walter J, Karnatz N, Lamszus K, Rogiers X, Broering DC (2007) Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment. Am J Pathol 171(5):1608–1618

    Article  PubMed  CAS  Google Scholar 

  • Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, Shimotohno K (2006) Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 25(17):2537–2545

    Article  PubMed  CAS  Google Scholar 

  • Murata K, Suzuki H, Okano H, Oyamada T, Yasuda Y, Sakamoto A (2010) Hypoxia-induced des-γ-carboxy prothrombin production in hepatocellular carcinoma. Int J Oncol 36(1):161–170

    PubMed  CAS  Google Scholar 

  • Nagoev BS, Abidov MT, Ivanova MR (2002) LPO and free-radical oxidation parameters in patients with acute viral hepatitis. Bull Exp Biol Med 134(6):557–558

    Article  PubMed  CAS  Google Scholar 

  • Nakagawa H, Maeda S, Yoshida H, Tateishi R, Masuzaki R, Ohki T, Hayakawa Y, Kinoshita H, Yamakado M, Kato N, Shiina S, Omata M (2009) Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences. Int J Cancer 125(10):2264–2269

    Article  PubMed  CAS  Google Scholar 

  • Nakazaki H (1992) Preoperative and postoperative cytokines in patients with cancer. Cancer 70(3):709–713

    Article  PubMed  CAS  Google Scholar 

  • Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317(5834):121–124

    Article  PubMed  CAS  Google Scholar 

  • Negrini M, Gramantieri L, Sabbioni S, Croce CM (2011) microRNA involvement in hepatocellular carcinoma. Anticancer Agents Med Chem 11(6):500–521

    Article  PubMed  CAS  Google Scholar 

  • Niu RF, Zhang L, Xi GM, Wei XY, Yang Y, Shi YR, Hao XS (2007) Up-regulation of Twist induces angiogenesis and correlates with metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res 26(3):385–394

    PubMed  CAS  Google Scholar 

  • Nkabyo YS, Ziegler TR, Gu LH, Watson WH, Jones DP (2002) Glutathione and thioredoxin redox during differentiation in human colon epithelial (Caco-2) cells. Am J Physiol Gastrointest Liver Physiol 283(6):G1352–G1359

    PubMed  CAS  Google Scholar 

  • Nordenstedt H, White DL, El-Serag HB (2010) The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis 42(Suppl 3):S206–S214

    Article  PubMed  Google Scholar 

  • O’Beirne J, Farzaneh F, Harrison PM (2010) Generation of functional CD8+ T cells by human dendritic cells expressing glypican-3 epitopes. J Exp Clin Cancer Res 29(1):48

    Article  PubMed  CAS  Google Scholar 

  • O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435(7043):839–843

    Article  PubMed  CAS  Google Scholar 

  • Padgett KA, Lan RY, Leung PC, Lleo A, Dawson K, Pfeiff J, Mao TK, Coppel RL, Ansari AA, Gershwin ME (2009) Primary biliary cirrhosis is associated with altered hepatic microRNA expression. J Autoimmun 32(3–4):246–253

    Article  PubMed  CAS  Google Scholar 

  • Pang RW, Poon RT (2007) From molecular biology to targeted therapies for hepatocellular carcinoma: the future is now. Oncology 72(Suppl 1):30–44

    Article  PubMed  CAS  Google Scholar 

  • Pardee AD, Butterfield LH (2012) Immunotherapy of hepatocellular carcinoma: unique challenges and clinical opportunities. Oncoimmunology 1(1):48–55

    Article  PubMed  Google Scholar 

  • Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M (2007) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140(2):197–208

    Article  CAS  Google Scholar 

  • Piao LS, Hur W, Kim TK, Hong SW, Kim SW, Choi JE, Sung PS, Song MJ, Lee BC, Hwang D, Yoon SK (2012) CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer Lett 315(2):129–137

    Article  PubMed  CAS  Google Scholar 

  • Pietras K, Ostman A (2010) Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316(8):1324–1331

    Article  PubMed  CAS  Google Scholar 

  • Pimienta G, Pascual J (2007) Canonical and alternative MAPK signaling. Cell Cycle 6(21):2628–2632

    Article  PubMed  CAS  Google Scholar 

  • Pleschka S (2008) RNA viruses and the mitogenic Raf/MEK/ERK signal transduction cascade. Biol Chem 389(10):1273–1282

    Article  PubMed  CAS  Google Scholar 

  • Pogribny IP, Starlard-Davenport A, Tryndyak VP, Han T, Ross SA, Rusyn I, Beland FA (2010) Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice. Lab Invest 90(10):1437–1446

    Article  PubMed  CAS  Google Scholar 

  • Polakis P (2012) Wnt signaling in cancer. Cold Spring Harb Perspect Biol 4(5):pii: a008052

    Google Scholar 

  • Ramaiah SK, Rittling S (2008) Pathophysiological role of osteopontin in hepatic inflammation, toxicity, and cancer. Toxicol Sci 103(1):4–13

    Article  PubMed  CAS  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111

    Article  PubMed  CAS  Google Scholar 

  • Rinaldi M, Iurescia S, Fioretti D, Ponzetto A, Carloni G (2009) Strategies for successful vaccination against hepatocellular carcinoma. Int J Immunopathol Pharmacol 22(2):269–277

    PubMed  CAS  Google Scholar 

  • Röring M, Brummer T (2012) Aberrant B-Raf signaling in human cancer—10 years from bench to bedside. Crit Rev Oncog 17(1):97–121

    Article  PubMed  Google Scholar 

  • Roskams T, Kojiro M (2010) Pathology of early hepatocellular carcinoma: conventional and molecular diagnosis. Semin Liver Dis 31(1):17–25

    Article  Google Scholar 

  • Saddic LA, Wirt S, Vogel H, Felsher DW, Sage J (2011) Functional interactions between retinoblastoma and c-MYC in a mouse model of hepatocellular carcinoma. PLoS ONE 6(5):e19758

    Article  PubMed  CAS  Google Scholar 

  • Salnikov AV, Kusumawidjaja G, Rausch V, Bruns H, Gross W, Khamidjanov A, Ryschich E, Gebhard MM, Moldenhauer G, Büchler MW, Schemmer P, Herr I (2009) Cancer stem cell marker expression in hepatocellular carcinoma and liver metastases is not sufficient as single prognostic parameter. Cancer Lett 275(2):185–193

    Article  PubMed  CAS  Google Scholar 

  • Schiffer EHC, Cacheux W, Wendum D, Desbois-Mouthon C, Rey C, Clergue F, Poupon R, Barbu V, Rosmorduc O (2005) Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 41(2):307–314

    Article  PubMed  CAS  Google Scholar 

  • Schrader J, Iredale JP (2011) The inflammatory microenvironment of HCC - the plot becomes complex. J Hepatol 54(5):853–855

    Article  PubMed  Google Scholar 

  • Schulze-Bergkamen H, Fleischer B, Schuchmann M, Weber A, Weinmann A, Krammer PH, Galle PR (2006) Suppression of Mcl-1 via RNA interference sensitizes human hepatocellular carcinoma cells towards apoptosis induction. BMC Cancer 6:232

    Article  PubMed  CAS  Google Scholar 

  • Severi T, van Malenstein H, Verslype C, van Pelt JF (2010) Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets. Acta Pharmacol Sin 31(11):1409–1420

    Article  PubMed  CAS  Google Scholar 

  • Shi GM, Xu Y, Fan J, Zhou J, Yang XR, Qiu SJ, Liao Y, Wu WZ, Ji Y, Ke AW, Ding ZB, He YZ, Wu B, Yang GH, Qin WZ, Zhang W, Zhu J, Min ZH, Wu ZQ (2008) Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials. J Cancer Res Clin Oncol 134(11):1155–1163

    Article  PubMed  CAS  Google Scholar 

  • Shimizu S, Takehara T, Hikita H, Kodama T, Tsunematsu H, Miyagi T, Hosui A, Ishida H, Tatsumi T, Kanto T, Hiramatsu N, Fujita N, Yoshimori T, Hayashi N (2012) Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma. Int J Cancer 131(3):548–557

    Article  PubMed  CAS  Google Scholar 

  • Shimoda R, Nagashima M, Sakamoto M, Yamaguchi N, Hirohashi S, Yokota J, Kasai H (1994) Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res 54(12):3171–3172

    PubMed  CAS  Google Scholar 

  • Shirakawa H, Suzuki H, Shimomura M, Kojima M, Gotohda N, Takahashi S, Nakagohri T, Konishi M, Kobayashi N, Kinoshita T, Nakatsura T (2009) Glypican-3 expression is correlated with poor prognosis in hepatocellular carcinoma. Cancer Sci 100(8):1403–1407

    Article  PubMed  CAS  Google Scholar 

  • Song J, Qu Z, Guo X, Zhao Q, Zhao X, Gao L, Sun K, Shen F, Wu M, Wei L (2009) Hypoxia-induced autophagy contributes to the chemoresistance of hepatocellular carcinoma cells. Autophagy 5(8):1131–1144

    Article  PubMed  CAS  Google Scholar 

  • Stahl S, Ittrich C, Marx-Stoelting P, Köhle C, Altug-Teber O, Riess O, Bonin M, Jobst J, Kaiser S, Buchmann A, Schwarz M (2005) Genotype-phenotype relationships in hepatocellular tumors from mice and man. Hepatology 42(2):353–361

    Article  PubMed  CAS  Google Scholar 

  • Stegh AH (2012) Targeting the p53 signaling pathway in cancer therapy - the promises, challenges and perils. Expert Opin Ther Targets 16(1):67–83

    Article  PubMed  CAS  Google Scholar 

  • Su H, Yang JR, Xu T, Huang J, Xu L, Yuan Y, Zhuang SM (2009) MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res 69(3):1135–1142

    Article  PubMed  CAS  Google Scholar 

  • Suetsugu A, Nagaki M, Aoki H, Motohashi T, Kunisada T, Moriwaki H (2006) Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun 351(4):820–824

    Article  PubMed  CAS  Google Scholar 

  • Sun JC, Pan K, Chen MS, Wang QJ, Wang H, Ma HQ, Li YQ, Liang XT, Li JJ, Zhao JJ, Chen YB, Pang XH, Liu WL, Cao Y, Guan XY, Lian QZ, Xia JC (2010) Dendritic cells-mediated CTLs targeting hepatocellular carcinoma stem cells. Cancer Biol Ther 10(4):368–375

    Article  PubMed  CAS  Google Scholar 

  • Suo A, Zhang M, Yao Y, Zhang L, Huang C, Nan K, Zhang W (2012) Proteome analysis of the effects of sorafenib on human hepatocellular carcinoma cell line HepG2. Med Oncol 29(3):1827–1836

    Google Scholar 

  • Tanaka H, Fujita N, Sugimoto R, Urawa N, Horiike S, Kobayashi Y, Iwasa M, Ma N, Kawanishi S, Watanabe S, Kaito M, Takei Y (2008) Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C. Br J Cancer 98(3):580–586

    Article  PubMed  CAS  Google Scholar 

  • Theise ND, Yao JL, Harada K, Hytiroglou P, Portmann B, Thung SN, Tsui W, Ohta H, Nakanuma Y (2003) Hepatic ‘stem cell’ malignancies in adults: four cases. Histopathology 43(3):263–271

    Article  PubMed  CAS  Google Scholar 

  • Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890

    Article  PubMed  CAS  Google Scholar 

  • Tomuleasa C, Soritau O, Rus-Ciuca D, Pop T, Todea D, Mosteanu O, Pintea B, Foris V, Susman S, Kacsó G, Irimie A (2010) Isolation and characterization of hepatic cancer cells with stem-like properties from hepatocellular carcinoma. J Gastrointesin Liver Dis 19(1):61–67

    Google Scholar 

  • Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3(2):133–146

    Article  PubMed  CAS  Google Scholar 

  • Tsai SM, Lin SK, Lee KT, Hsiao JK, Huang JC, Wu SH, Ma H, Wu SH, Tsai LY (2009a) Evaluation of redox statuses in patients with hepatitis B virus-associated hepatocellular carcinoma. Ann Clin Biochem 46(Pt 5):394–400

    Article  PubMed  CAS  Google Scholar 

  • Tsai WC, Hsu PW, Lai TC, Chau GY, Lin CW, Chen CM, Lin CD, Liao YL, Wang JL, Chau YP, Hsu MT, Hsiao M, Huang HD, Tsou AP (2009b) MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology 49(5):1571–1582

    Article  PubMed  CAS  Google Scholar 

  • Ura S, Honda M, Yamashita T, Ueda T, Takatori H, Nishino R, Sunakozaka H, Sakai Y, Horimoto K, Kaneko S (2009) Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma. Hepatology 49(4):1098–1112

    Article  PubMed  CAS  Google Scholar 

  • van Kouwenhove M, Kedde M, Agami R (2011) MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat Rev Cancer 11(9):644–656

    Article  PubMed  CAS  Google Scholar 

  • van Malenstein H, Gevaert O, Libbrecht L, Daemen A, Allemeersch J, Nevens F, Van Cutsem E, Cassiman D, De Moor B, Verslype C, van Pelt J (2010) A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma. Clin Cancer Res 16(16):4278–4288

    Article  PubMed  CAS  Google Scholar 

  • van Zijl F, Mair M, Csiszar A, Schneller D, Zulehner G, Huber H, Eferl R, Beug H, Dolznig H, Mikulits W (2009a) Hepatic tumor-stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge. Oncogene 28(45):4022–4033

    Article  PubMed  CAS  Google Scholar 

  • van Zijl F, Zulehner G, Petz M, Schneller D, Kornauth C, Hau M, Machat G, Grubinger M, Huber H, Mikulits W (2009b) Epithelial-mesenchymal transition in hepatocellular carcinoma. Future Oncol 5(8):1169–1179

    Article  PubMed  Google Scholar 

  • Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8(10):755–768

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Kato N, Hoshida Y, Yoshida H, Taniguchi H, Goto T, Moriyama M, Otsuka M, Shiina S, Shiratori Y, Ito Y, Omata M (2003) Interleukin-1β gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology 37(1):65–71

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Lee AT, Ma JZ, Wang J, Ren J, Yang Y, Tantoso E, Li KB, Ooi LL, Tan P, Lee CG (2008) Profiling microRNA expression in hepatocellular carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224-specific target. J Biol Chem 283(19):13205–13215

    Article  PubMed  CAS  Google Scholar 

  • Wang F, Jing X, Li G, Wang T, Yang B, Zhu Z, Gao Y, Zhang Q, Yang Y, Wang Y, Wang P, Du Z (2012) Foxp3 + regulatory T cells are associated with the natural history of chronic hepatitis B and poor prognosis of hepatocellular carcinoma. Liver Int 32(4):644–655

    Article  PubMed  CAS  Google Scholar 

  • Wheelhouse NM, Chan YS, Gillies SE, Caldwell H, Ross JA, Harrison DJ, Prost S (2003) TNF-α induced DNA damage in primary murine hepatocytes. Int J Mol Med 12(6):889–894

    PubMed  CAS  Google Scholar 

  • White LA, Menzin J, Korn JR, Friedman M, Lang K, Ray S (2012) Medical care costs and survival associated with hepatocellular carcinoma among the elderly. Clin Gastroenterol Hepatol 10(5):547–554

    Article  PubMed  Google Scholar 

  • Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109

    Article  PubMed  CAS  Google Scholar 

  • Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5(10):835–844

    Article  PubMed  CAS  Google Scholar 

  • Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, Wong N (2008) MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of stathmin1. Gastroenterology 135(1):257–269

    Article  PubMed  CAS  Google Scholar 

  • Wong VW, Yu J, Cheng AS, Wong GL, Chan HY, Chu ES, Ng EK, Chan FK, Sung JJ, Chan HL (2009) High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. Int J Cancer 124(12):2766–2770

    Article  PubMed  CAS  Google Scholar 

  • Wu K, Kryczek I, Chen L, Zou W, Welling TH (2009) Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7–H1/programmed death-1 interactions. Cancer Res 69(20):8067–8075

    Article  PubMed  CAS  Google Scholar 

  • Wu SD, Ma YS, Fang Y, Liu LL, Fu D, Shen XZ (2012) Role of the microenvironment in hepatocellular carcinoma development and progression. Cancer Treat Rev 38(3):218–225

    Article  PubMed  CAS  Google Scholar 

  • Yam JW, Wong CM, Ng IO (2010) Molecular and functional genetics of hepatocellular carcinoma. Front Biosci (Schol Ed) 2:117–134

    Article  Google Scholar 

  • Yamashita YI, Shimada M, Hasegawa H, Minagawa R, Rikimaru T, Hamatsu T, Tanaka S, Shirabe K, Miyazaki JI, Sugimachi K (2001) Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma in the mice model. Cancer Res 61(3):1005–1012

    PubMed  CAS  Google Scholar 

  • Yan W, Fu Y, Tian D, Liao J, Liu M, Wang B, Xia L, Zhu Q, Luo M (2009) PI3 kinase/Akt signaling mediates epithelial-mesenchymal transition in hypoxic hepatocellular carcinoma cells. Biochem Biophys Res Commun 382(3):631–636

    Article  PubMed  CAS  Google Scholar 

  • Yan W, Chang Y, Liang X, Cardinal JS, Huang H, Thorne SH, Monga SP, Geller DA, Lotze MT, Tsung A (2012) High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology 55(6):1863–1875

    Article  PubMed  CAS  Google Scholar 

  • Yang J, Zhou F, Xu T, Deng H, Ge YY, Zhang C, Li J, Zhuang SM (2008a) Analysis of sequence variations in 59 microRNAs in hepatocellular carcinomas. Mutat Res 638(1–2):205–209

    PubMed  CAS  Google Scholar 

  • Yang ZF, Ngai P, Ho DW, Yu WC, Ng MN, Lau CK, Li ML, Tam KH, Lam CT, Poon RT, Fan ST (2008b) Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 47(3):919–928

    Article  PubMed  CAS  Google Scholar 

  • Yang MH, Chen CL, Chau GY, Chiou SH, Su CW, Chou TY, Peng WL, Wu JC (2009) Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology 50(5):1464–1474

    Article  PubMed  CAS  Google Scholar 

  • Yang JD, Nakamura I, Roberts LR (2011) The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol 21(1):35–43

    Article  PubMed  CAS  Google Scholar 

  • Yasuda E, Kumada T, Takai S, Ishisaki A, Noda T, Matsushima-Nishiwaki R, Yoshimi N, Kato K, Toyoda H, Kaneoka Y, Yamaguchi A, Kozawa O (2005) Attenuated phosphorylation of heat shock protein 27 correlates with tumor progression in patients with hepatocellular carcinoma. Biochem Biophys Res Commun 337(1):337–342

    Article  PubMed  CAS  Google Scholar 

  • Yin S, Li J, Hu C, Chen X, Yao M, Yan M, Jiang G, Ge C, Xie H, Wan D, Yang S, Zheng S, Gu J (2007) CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 120(7):1444–1450

    Article  PubMed  CAS  Google Scholar 

  • Yoshida T, Hisamoto T, Akiba J, Koga H, Nakamura K, Tokunaga Y, Hanada S, Kumemura H, Maeyama M, Harada M, Ogata H, Yano H, Kojiro M, Ueno T, Yoshimura A, Sata M (2006) Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors. Oncogene 25(45):6056–6066

    Article  PubMed  CAS  Google Scholar 

  • Yoshiji H, Noguchi R, Kuriyama S, Yoshii J, Ikenaka Y, Yanase K, Namisaki T, Kitade M, Yamazaki M, Uemura M, Fukui H (2005) Different cascades in the signaling pathway of two vascular endothelial growth factor (VEGF) receptors for the VEGF-mediated murine hepatocellular carcinoma development. Oncol Rep 13(5):853–857

    PubMed  CAS  Google Scholar 

  • Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Yang B, Du Z, Bai T, Gao YT, Wang YJ, Lou C, Wang FM, Bai Y (2007) Aberrant methylation of SPARC in human hepatocellular carcinoma and its clinical implication. World J Gastroenterol 18(17):2043–2052

    Article  CAS  Google Scholar 

  • Zhao LJ, Wang L, Ren H, Cao J, Li L, Ke JS, Qi ZT (2005) Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors. Exp Cell Res 305(1):23–32

    Article  PubMed  CAS  Google Scholar 

  • Zheng FQ, Xu Y, Yang RJ, Wu B, Tan XH, Qin YD, Zhang QW (2009) Combination effect of oncolytic adenovirus therapy and herpes simplex virus thymidine kinase/ganciclovir in hepatic carcinoma animal models. Acta Pharmacol Sin 30(5):617–627

    Article  PubMed  CAS  Google Scholar 

  • Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, Li J (2010) Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma. Int J Cancer 126(9):2067–2078

    PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rajagopal N. Aravalli.

Additional information

We apologize to the authors whose works were not cited due to the limitations of length and the number of references.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aravalli, R.N., Cressman, E.N.K. & Steer, C.J. Cellular and molecular mechanisms of hepatocellular carcinoma: an update. Arch Toxicol 87, 227–247 (2013). https://doi.org/10.1007/s00204-012-0931-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-012-0931-2

Keywords

Navigation