Inflammation and liver tumorigenesis

Abstract

Inflammation has been considered as one of the hallmarks of cancer, and chronic hepatitis is a major cause of liver cancer. This review will focus on the pathogenic role of inflammation in hepatocarcinogenesis and will discuss recent advances in understanding the chronic hepatitis-liver cancer link based on hot spots in liver cancer research, including cellular interaction, cytokines, microRNA and stem cells. All of these mechanisms should be taken into consideration because they are crucial for the development of more efficacious therapeutic strategies for preventing and treating human chronic hepatitis and hepatocellular carcinoma.

Keywords

hepatocellular carcinoma / hepatitis / cytokine / stem cell / miRNA

References

[1] Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene2008; 27(45): 5904-5912

[2] Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, Gupta S, Moore J, Wrobel MJ, Lerner J, Reich M, Chan JA, Glickman JN, Ikeda K, Hashimoto M, Watanabe G, Daidone MG, Roayaie S, Schwartz M, Thung S, Salvesen HB, Gabriel S, Mazzaferro V, Bruix J, Friedman SL, Kumada H, Llovet JM, Golub TR. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med2008; 359(19): 1995-2004

[3] Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene2006; 25(27): 3834-3847

[4] Sweet MJ, Hume DA. Endotoxin signal transduction in macrophages. J Leukoc Biol1996; 60(1): 8-26

[5] Yan S, Wang L, Liu N, Wang Y, Chu Y. Critical role of interleukin-17/interleukin-17 receptor axis in mediating Con A-induced hepatitis. Immunol Cell Biol2012; 90(4): 421-428

[6] Hsieh WT, Tsai CT, Wu JB, Hsiao HB, Yang LC, Lin WC. Kinsenoside, a high yielding constituent from Anoectochilus formosanus, inhibits carbon tetrachloride induced Kupffer cells mediated liver damage. J Ethnopharmacol2011; 135(2): 440-449

[7] Ramaiah SK, Jaeschke H. Role of neutrophils in the pathogenesis of acute inflammatory liver injury. Toxicol Pathol2007; 35(6): 757-766

[8] Jaeschke H, Hasegawa T. Role of neutrophils in acute inflammatory liver injury. Liver Int2006; 26(8): 912-919

[9] Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. Am J Physiol1991; 260(3 Pt 1): G355-G362

[10] Lee WM. Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure. Hepatology2004; 40(1): 6-9

[11] Knolle PA, Gerken G. Local control of the immune response in the liver. Immunol Rev2000;174:21-34

[12] Ishida Y, Kondo T, Ohshima T, Fujiwara H, Iwakura Y, Mukaida N. A pivotal involvement of IFN-gamma in the pathogenesis of acetaminophen-induced acute liver injury. FASEB J2002; 16(10): 1227-1236

[13] Liu ZX, Govindarajan S, Kaplowitz N. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology2004; 127(6): 1760-1774

[14] Arshad MI, Rauch M, L’helgoualc’h A, Julia V, Leite-de-Moraes MC, Lucas-Clerc C, Piquet-Pellorce C, Samson M. NKT cells are required to induce high IL-33 expression in hepatocytes during ConA-induced acute hepatitis. Eur J Immunol2011; 41(8): 2341-2348

[15] Bissell DM, Wang SS, Jarnagin WR, Roll FJ. Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest1995; 96(1): 447-455

[16] Knolle PA, Löser E, Protzer U, Duchmann R, Schmitt E, zum Büschenfelde KH, Rose-John S, Gerken G. Regulation of endotoxin-induced IL-6 production in liver sinusoidal endothelial cells and Kupffer cells by IL-10. Clin Exp Immunol1997; 107(3): 555-561

[17] Knolle PA, Germann T, Treichel U, Uhrig A, Schmitt E, Hegenbarth S, Lohse AW, Gerken G. Endotoxin down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells. J Immunol1999; 162(3): 1401-1407

[18] Knolle PA, Limmer A. Neighborhood politics: the immunoregulatory function of organ-resident liver endothelial cells. Trends Immunol2001; 22(8): 432-437

[19] Knolle PA, Uhrig A, Hegenbarth S, Löser E, Schmitt E, Gerken G, Lohse AW. IL-10 down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells through decreased antigen uptake via the mannose receptor and lowered surface expression of accessory molecules. Clin Exp Immunol1998; 114(3): 427-433

[20] Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol2009; 27: 147-163

[21] Kojima N, Sato M, Suzuki A, Sato T, Satoh S, Kato T, Senoo H. Enhanced expression of B7-1, B7-2, and intercellular adhesion molecule 1 in sinusoidal endothelial cells by warm ischemia/reperfusion injury in rat liver. Hepatology2001; 34(4): 751-757

[22] Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, Hussell T, Feldmann M, Udalova IA. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol2011; 12(3): 231-238

[23] Chappell L, Kaiser P, Barrow P, Jones MA, Johnston C, Wigley P. The immunobiology of avian systemic salmonellosis. Vet Immunol Immunopathol2009; 128(1-3): 53-59

[24] Larrubia JR, Benito-Martínez S, Calvino M, Sanz-de-Villalobos E, Parra-Cid T. Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection. World J Gastroenterol2008; 14(47): 7149-7159

[25] Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol2008; 214(2): 199-210

[26] 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. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res2010; 70(14): 5728-5739

[27] Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol2010; 11(10): 889-896

[28] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell2010; 140(6): 883-899

[29] Karin M. Nuclear factor-kappaB in cancer development and progression. Nature2006; 441(7092): 431-436

[30] Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci2011; 7(5): 651-658

[31] Chen S, Akbar SM, Abe M, Hiasa Y, Onji M. Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus. Clin Exp Immunol2011; 166(1): 134-142

[32] Hu CE, Gan J, Zhang RD, Cheng YR, Huang GJ. Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function. Scand J Gastroenterol2011; 46(2): 156-164

[33] Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger C, Manns MP, Greten TF, Korangy F. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology2008; 135(1): 234-243

[34] Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, Lehner F, Manns MP, Greten TF, Korangy F. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology2009; 50(3): 799-807

[35] Grivennikov SI, Karin M. Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev2010; 20(1): 65-71

[36] Voloboueva LA, Giffard RG. Inflammation, mitochondria, and the inhibition of adult neurogenesis. J Neurosci Res2011; 89(12): 1989-1996

[37] Tawara K, Oxford JT, Jorcyk CL. Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Manag Res2011;3:177-189

[38] Tanaka T, Narazaki M, Kishimoto T. Therapeutic Targeting of the Interleukin-6 Receptor. Annu Rev Pharmacol Toxicol2012; 52: 199-219

[39] Mair M, Blaas L, Osterreicher CH, Casanova E, Eferl R. JAK-STAT signaling in hepatic fibrosis. Front Biosci2011; 17: 2794-2811

[40] Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest2011; 121(9): 3375-3383

[41] Erreni M, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) and inflammation in colorectal cancer. Cancer Microenviron2011; 4(2): 141-154

[42] Wang YC, Xu GL, Jia WD, Han SJ, Ren WH, Wang W, Liu WB, Zhang CH, Chen H. Estrogen suppresses metastasis in rat hepatocellular carcinoma through decreasing interleukin-6 and hepatocyte growth factor expression. Inflammation2012; 35(1): 143-149

[43] Jiang R, Deng L, Zhao L, Li X, Zhang F, Xia Y, Gao Y, Wang X, Sun B. miR-22 promotes HBV-related hepatocellular carcinoma development in males. Clin Cancer Res2011; 17(17): 5593-5603

[44] Hsu SH, Wang LT, Lee KT, Chen YL, Liu KY, Suen JL, Chai CY, Wang SN. Pro-inflammatory homeobox gene, ISX, regulates tumor growth and survival in hepatocellular carcinoma. Cancer Res Cancer Res2013; 73(2): 508-518

[45] Kroy DC, Beraza N, Tschaharganeh DF, Sander LE, Erschfeld S, Giebeler A, Liedtke C, Wasmuth HE, Trautwein C, Streetz KL. Lack of interleukin-6/glycoprotein 130/signal transducers and activators of transcription-3 signaling in hepatocytes predisposes to liver steatosis and injury in mice. Hepatology2010; 51(2): 463-473

[46] Ando M, Uehara I, Kogure K, Asano Y, Nakajima W, Abe Y, Kawauchi K, Tanaka N. Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3. J Nippon Med Sch2010; 77(2): 97-105

[47] Liu Y, Li PK, Li C, Lin J. Inhibition of STAT3 signaling blocks the anti-apoptotic activity of IL-6 in human liver cancer cells. J Biol Chem2010; 285(35): 27429-27439

[48] Alison MR, Nicholson LJ, Lin WR. Chronic inflammation and hepatocellular carcinoma. Recent Results Cancer Res2011; 185: 135-148

[49] Sander LE, Sackett SD, Dierssen U, Beraza N, Linke RP, Müller M, Blander JM, Tacke F, Trautwein C. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. J Exp Med2010; 207(7): 1453-1464

[50] Kushibiki S. Tumor necrosis factor-α-induced inflammatory responses in cattle. Anim Sci J2011; 82(4): 504-511

[51] Caminero A, Comabella M, Montalban X. Tumor necrosis factor alpha (TNF-α), anti-TNF-α and demyelination revisited: an ongoing story. J Neuroimmunol2011; 234(1-2): 1-6

[52] Shukla R, Yue J, Siouda M, Gheit T, Hantz O, Merle P, Zoulim F, Krutovskikh V, Tommasino M, Sylla BS. Proinflammatory cytokine TNF-α increases the stability of hepatitis B virus X protein through NF-κB signaling. Carcinogenesis2011; 32(7): 978-985

[53] Shi Z, Du C. Tumor necrosis factor alpha 308 G/A polymorphism and hepatocellular carcinoma risk in a Chinese population. Genet Test Mol Biomarkers2011; 15(7-8): 569-572

[54] Wang B, Wang J, Zheng Y, Zhou S, Zheng J, Wang F, Ma X, Zeng Z. A study of TNF-alpha-238 and-308 polymorphisms with different outcomes of persistent hepatitis B virus infection in China. Pathology2010; 42(7): 674-680

[55] Chen KF, Tai WT, Liu TH, Huang HP, Lin YC, Shiau CW, Li PK, Chen PJ, Cheng AL. Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res2010; 16(21): 5189-5199

[56] Xia L, Mo P, Huang W, Zhang L, Wang Y, Zhu H, Tian D, Liu J, Chen Z, Zhang Y, Chen Z, Hu H, Fan D, Nie Y, Wu K. The TNF-α/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis. Carcinogenesis2012; 33(11): 2250-2259

[57] Muntané J. Targeting cell death and survival receptors in hepatocellular carcinoma. Anticancer Agents Med Chem2011; 11(6): 576-584

[58] Kriegl L, Jung A, Engel J, Jackstadt R, Gerbes AL, Gallmeier E, Reiche JA, Hermeking H, Rizzani A, Bruns CJ, Kolligs FT, Kirchner T, Göke B, De Toni EN. Expression, cellular distribution, and prognostic relevance of TRAIL receptors in hepatocellular carcinoma. Clin Cancer Res2010; 16(22): 5529-5538

[59] Giannelli G, Mazzocca A, Fransvea E, Lahn M, Antonaci S. Inhibiting TGF-β signaling in hepatocellular carcinoma. Biochim Biophys Acta2011; 1815(2): 214-223

[60] Achyut BR, Yang L. Transforming growth factor-β in the gastrointestinal and hepatic tumor microenvironment. Gastroenterology2011; 141(4): 1167-1178

[61] Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol2006; 7(2): 131-142

[62] Coulouarn C, Factor VM, Thorgeirsson SS. Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology2008; 47(6): 2059-2067

[63] Mamiya T, Yamazaki K, Masugi Y, Mori T, Effendi K, Du W, Hibi T, Tanabe M, Ueda M, Takayama T, Sakamoto M. Reduced transforming growth factor-beta receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis. Lab Invest2010; 90(9): 1339-1345

[64] Ito N, Kawata S, Tamura S, Shirai Y, Kiso S, Tsushima H, Matsuzawa Y. Positive correlation of plasma transforming growth factor-beta 1 levels with tumor vascularity in hepatocellular carcinoma. Cancer Lett1995; 89(1): 45-48

[65] Mazzocca A, Fransvea E, Lavezzari G, Antonaci S, Giannelli G. Inhibition of transforming growth factor beta receptor I kinase blocks hepatocellular carcinoma growth through neo-angiogenesis regulation. Hepatology2009; 50(4): 1140-1151

[66] Wu K, Ding J, Chen C, Sun W, Ning BF, Wen W, Huang L, Han T, Yang W, Wang C, Li Z, Wu MC, Feng GS, Xie WF, Wang HY. Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development. Hepatology2012; 56(6): 2255-2267

[67] Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol2005; 6(11): 1133-1141

[68] Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol2007; 25: 821-852

[69] Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity2004; 21(4): 467-476

[70] Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol2008; 8(5): 337-348

[71] Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, Soumelis V. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol2008; 9(6): 650-657

[72] Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol2008; 9(6): 641-649

[73] Notley CA, Inglis JJ, Alzabin S, McCann FE, McNamee KE, Williams RO. Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells. J Exp Med2008; 205(11): 2491-2497

[74] Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, Wu C, Li SP, Zheng L. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol2009; 50(5): 980-989

[75] Laan M, Cui ZH, Hoshino H, Lötvall J, Sjöstrand M, Gruenert DC, Skoogh BE, Lindén A. Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol1999; 162(4): 2347-2352

[76] Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer2008; 8(8): 618-631

[77] Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology2010; 51(1): 154-164

[78] Zhao Q, Xiao X, Wu Y, Wei Y, Zhu LY, Zhou J, Kuang DM. Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients. Eur J Immunol2011; 41(8): 2314-2322

[79] Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity2000; 13(5): 715-725

[80] Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med2003; 198(12): 1951-1957

[81] Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F, Maloy KJ. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med2006; 203(11): 2473-2483

[82] Lo CH, Chang CM, Tang SW, Pan WY, Fang CC, Chen Y, Wu PY, Chen KY, Ma HI, Xiao X, Tao MH. Differential antitumor effect of interleukin-12 family cytokines on orthotopic hepatocellular carcinoma. J Gene Med2010; 12(5): 423-434

[83] Hu P, Hu HD, Chen M, Peng ML, Tang L, Tang KF, Matsui M, Belladonna ML, Yoshimoto T, Zhang DZ, Xiang R, Ren H. Expression of interleukins-23 and 27 leads to successful gene therapy of hepatocellular carcinoma. Mol Immunol2009; 46(8-9): 1654-1662

[84] Li J, Lau G, Chen L, Yuan YF, Huang J, Luk JM, Xie D, Guan XY. Interleukin 23 promotes hepatocellular carcinoma metastasis via NF-kappa B induced matrix metalloproteinase 9 expression. PLoS ONE2012; 7(9): e46264

[85] Jiang R, Tan Z, Deng L, Chen Y, Xia Y, Gao Y, Wang X, Sun B. Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology2011; 54(3): 900-909

[86] Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. J Biol Chem2002; 277(37): 33676-33682

[87] Zhang W, Chen Y, Wei H, Zheng C, Sun R, Zhang J, Tian Z. Antiapoptotic activity of autocrine interleukin-22 and therapeutic effects of interleukin-22-small interfering RNA on human lung cancer xenografts. Clin Cancer Res2008; 14(20): 6432-6439

[88] Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity2007; 27(4): 647-659

[89] Park O, Wang H, Weng H, Feigenbaum L, Li H, Yin S, Ki SH, Yoo SH, Dooley S, Wang FS, Young HA, Gao B. In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression. Hepatology2011; 54(1): 252-261

[90] Bertino G, Ardiri A, Malaguarnera M, Malaguarnera G, Bertino N, Calvagno GS. Hepatocellualar carcinoma serum markers. Semin Oncol2012; 39(4): 410-433

[91] Hu J, Xu Y, Hao J, Wang S, Li C, Meng S. MiR-122 in hepatic function and liver diseases. Protein Cell2012; 3(5): 364-371

[92] Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell2004; 116(2): 281-297

[93] He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet2004; 5(7): 522-531

[94] Sugatani T, Hruska KA. Down-regulation of miR-21 biogenesis by estrogen action contributes to osteoclastic apoptosis. J Cell Biochem2012; n/a

[95] Mott JL. MicroRNAs involved in tumor suppressor and oncogene pathways: implications for hepatobiliary neoplasia. Hepatology2009; 50(2): 630-637

[96] Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S, Zucman-Rossi J. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology2008; 47(6): 1955-1963

[97] Braconi C, Patel T. MicroRNA expression profiling: a molecular tool for defining the phenotype of hepatocellular tumors. Hepatology2008; 47(6): 1807-1809

[98] Jiang J, Gusev Y, Aderca I, Mettler TA, Nagorney DM, Brackett DJ, Roberts LR, Schmittgen TD. Association of microRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res2008; 14(2): 419-427

[99] Kutay H, Bai S, Datta J, Motiwala T, Pogribny I, Frankel W, Jacob ST, Ghoshal K. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem2006; 99(3): 671-678

[100] Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, Shimotohno K. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene2006; 25(17): 2537-2545

[101] 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. Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma. Int J Cancer2008; 123(7): 1616-1622

[102] Wang Y, Lee AT, Ma JZ, Wang J, Ren J, Yang Y, Tantoso E, Li KB, Ooi LL, Tan P, Lee CG. Profiling microRNA expression in hepatocellular carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224-specific target. J Biol Chem2008; 283(19): 13205-13215

[103] Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, Zanetti KA, Ye QH, Qin LX, Croce CM, Tang ZY, Wang XW. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology2008; 47(3): 897-907

[104] 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. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res2007; 67(13): 6092-6099

[105] Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M. MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology2008; 47(4): 1223-1232

[106] Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, Wong N. MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology2008; 135(1): 257-269

[107] Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B, Mazzaferro V, Lowe SW, Croce CM, Dejean A. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci USA2010; 107(1): 264-269

[108] Fan CG, Wang CM, Tian C, Wang Y, Li L, Sun WS, Li RF, Liu YG. miR-122 inhibits viral replication and cell proliferation in hepatitis B virus-related hepatocellular carcinoma and targets NDRG3. Oncol Rep2011; 26(5): 1281-1286

[109] Pedersen IM, Cheng G, Wieland S, Volinia S, Croce CM, Chisari FV, David M. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature2007; 449(7164): 919-922

[110] Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science2005; 309(5740): 1577-1581

[111] Zhang X, Zhang E, Ma Z, Pei R, Jiang M, Schlaak JF, Roggendorf M, Lu M. Modulation of hepatitis B virus replication and hepatocyte differentiation by microRNA-1. Hepatology2011; 53(5): 1476-1485

[112] Sarasin-Filipowicz M, Krol J, Markiewicz I, Heim MH, Filipowicz W. Decreased levels of microRNA miR-122 in individuals with hepatitis C responding poorly to interferon therapy. Nat Med2009; 15(1): 31-33

[113] van der Poorten D, George J. Disease-specific mechanisms of fibrosis: hepatitis C virus and nonalcoholic steatohepatitis. Clin Liver Dis2008; 12(4): 805-824, ix (ix.)

[114] Whittaker R, Loy PA, Sisman E, Suyama E, Aza-Blanc P, Ingermanson RS, Price JH, McDonough PM. Identification of microRNAs that control lipid droplet formation and growth in hepatocytes via high-content screening. J Biomol Screen2010; 15(7): 798-805

[115] Zheng L, Lv GC, Sheng J, Yang YD. Effect of miRNA-10b in regulating cellular steatosis level by targeting PPAR-alpha expression, a novel mechanism for the pathogenesis of NAFLD. J Gastroenterol Hepatol2010; 25(1): 156-163

[116] Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, Kellum JM, Min H, Luketic VA, Sanyal AJ. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology2008; 48(6): 1810-1820

[117] Song G, Sharma AD, Roll GR, Ng R, Lee AY, Blelloch RH, Frandsen NM, Willenbring H. MicroRNAs control hepatocyte proliferation during liver regeneration. Hepatology2010; 51(5): 1735-1743

[118] Castro RE, Ferreira DM, Zhang X, Borralho PM, Sarver AL, Zeng Y, Steer CJ, Kren BT, Rodrigues CM. Identification of microRNAs during rat liver regeneration after partial hepatectomy and modulation by ursodeoxycholic acid. Am J Physiol Gastrointest Liver Physiol2010; 299(4): G887-G897

[119] Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology2007; 133(2): 647-658

[120] Marquez RT, Wendlandt E, Galle CS, Keck K, McCaffrey AP. MicroRNA-21 is upregulated during the proliferative phase of liver regeneration, targets Pellino-1, and inhibits NF-kappaB signaling. Am J Physiol Gastrointest Liver Physiol2010; 298(4): G535-G541

[121] Lowes KN, Brennan BA, Yeoh GC, Olynyk JK. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol1999; 154(2): 537-541

[122] Libbrecht L, Desmet V, Van Damme B, Roskams T. Deep intralobular extension of human hepatic ‘progenitor cells’ correlates with parenchymal inflammation in chronic viral hepatitis: can ‘progenitor cells’ migrate? J Pathol2000; 192(3): 373-378

[123] Viebahn CS, Yeoh GC. What fires prometheus? The link between inflammation and regeneration following chronic liver injury. Int J Biochem Cell Biol2008; 40(5): 855-873

[124] Alison MR, Lovell MJ. Liver cancer: the role of stem cells. Cell Prolif2005; 38(6): 407-421

[125] Theise ND, Yao JL, Harada K, Hytiroglou P, Portmann B, Thung SN, Tsui W, Ohta H, Nakanuma Y. Hepatic ‘stem cell’ malignancies in adults: four cases. Histopathology2003; 43(3): 263-271

[126] Dumble ML, Croager EJ, Yeoh GC, Quail EA. Generation and characterization of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma. Carcinogenesis2002; 23(3): 435-445

[127] Korkaya H, Wicha MS. Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs2007; 21(5): 299-310

[128] Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea—a paradigm shift. Cancer Res2006; 66(4): 1883-1890; discussion 1895-1896

[129] Vermeulen L, De Sousa E Melo F, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, Sprick MR, Kemper K, Richel DJ, Stassi G, Medema JP. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol2010; 12(5): 468-476

[130] Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and their microenvironment. Trends Genet2009; 25(1): 30-38

[131] Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M, Frank A, Bayazitov IT, Zakharenko SS, Gajjar A, Davidoff A, Gilbertson RJ. A perivascular niche for brain tumor stem cells. Cancer Cell2007; 11(1): 69-82

[132] Stauffer JK, Scarzello AJ, Andersen JB, De Kluyver RL, Back TC, Weiss JM, Thorgeirsson SS, Wiltrout RH. Coactivation of AKT and β-catenin in mice rapidly induces formation of lipogenic liver tumors. Cancer Res2011; 71(7): 2718-2727

[133] Schrader J, Gordon-Walker TT, Aucott RL, van Deemter M, Quaas A, Walsh S, Benten D, Forbes SJ, Wells RG, Iredale JP. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology2011; 53(4): 1192-1205

[134] Brunt EM, Blomenkamp K, Ahmed M, Ali F, Marcus N, Teckman J. Hepatic progenitor cell proliferation and liver injury in α-1-antitrypsin deficiency. J Pediatr Gastroenterol Nutr2010; 51(5): 626-630

[135] Kitisin K, Shetty K, Mishra L, Johnson LB. Hepatocellular stem cells. Cancer Biomark2007; 3(4-5): 251-262

[136] Yamashita T, Honda M, Nakamoto Y, Baba M, Nio K, Hara Y, Zeng SS, Hayashi T, Kondo M, Takatori H, Yamashita T, Mizukoshi E, Ikeda H, Zen Y, Takamura H, Wang XW, Kaneko S. Discrete nature of EpCAM(+) and CD90(+) cancer stem cells in human hepatocellular carcinoma. Hepatology2012; 57(4):1484-97

[137] Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, Browning B, Michaelson JS, Baetscher M, Wang B, Bissell DM, Burkly LC. TWEAK induces liver progenitor cell proliferation. J Clin Invest2005; 115(9): 2330-2340

[138] Fausto N. Tweaking liver progenitor cells. Nat Med2005; 11(10): 1053-1054

[139] Akhurst B, Matthews V, Husk K, Smyth MJ, Abraham LJ, Yeoh GC. Differential lymphotoxin-beta and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury. Hepatology2005; 41(2): 327-335

[140] Uchio K, Graham M, Dean NM, Rosenbaum J, Desmoulière A. Down-regulation of connective tissue growth factor and type I collagen mRNA expression by connective tissue growth factor antisense oligonucleotide during experimental liver fibrosis. Wound Repair Regen2004; 12(1): 60-66

[141] Nakamura K, Nonaka H, Saito H, Tanaka M, Miyajima A. Hepatocyte proliferation and tissue remodeling is impaired after liver injury in oncostatin M receptor knockout mice. Hepatology2004; 39(3): 635-644

[142] Brooling JT, Campbell JS, Mitchell C, Yeoh GC, Fausto N. Differential regulation of rodent hepatocyte and oval cell proliferation by interferon gamma. Hepatology2005; 41(4): 906-915

[143] Gangaraju VK, Lin H. MicroRNAs: key regulators of stem cells. Nat Rev Mol Cell Biol2009; 10(2): 116-125

[144] Osborne JD, Flatow J, Holko M, Lin SM, Kibbe WA, Zhu LJ, Danila MI, Feng G, and Chisholm RL. Annotating the human genome with Disease Ontology. BMC Genomics.2009;10Suppl 1(S6.

[145] 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. Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology2009; 50(2): 472-480

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