Nonalcoholic steatohepatitis and noncirrhotic hepatocellular carcinoma: Fertile soil

Seminars in Liver Disease

Volumn 32, Issue 1, 2012, Pages 30-38

  Torres, Dawn M ^a   Harrison, Stephen A ^b  

^a WALTER REED ARMY MEDICAL CENTER   (United States)

^b SAN ANTONIO MILITARY MEDICAL CENTER   (United States)

Author keywords

hepatocellular carcinoma; insulin resistance; Nonalcoholic fatty liver disease; nonalcoholic steatohepatitis

Indexed keywords

ADENOSINE PHOSPHATE; ADIPONECTIN; ANDROSTANE DERIVATIVE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INSULIN RECEPTOR SUBSTRATE 1; INTERLEUKIN 6; IRON; MICRORNA; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; STAT3 PROTEIN; STAT5 PROTEIN; STRESS ACTIVATED PROTEIN KINASE; TOLL LIKE RECEPTOR; TUMOR NECROSIS FACTOR ALPHA;

CANCER SCREENING; CLINICAL FEATURE; CROSS-SECTIONAL STUDY; DIABETES MELLITUS; HUMAN; INSULIN RESISTANCE; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; NONALCOHOLIC FATTY LIVER; OBESITY; OXIDATIVE STRESS; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; RISK FACTOR;

AMP-ACTIVATED PROTEIN KINASES; CARCINOMA, HEPATOCELLULAR; CELL TRANSFORMATION, NEOPLASTIC; CYTOKINES; DIABETES COMPLICATIONS; FATTY LIVER; HUMANS; INSULIN RESISTANCE; IRON OVERLOAD; LIVER NEOPLASMS; MICRORNAS; OBESITY; OXIDATIVE STRESS; PTEN PHOSPHOHYDROLASE; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RISK FACTORS; SIGNAL TRANSDUCTION; TOLL-LIKE RECEPTORS;

EID: 84857947511     PISSN: 02728087     EISSN: 10988971     Source Type: Journal    
DOI: 10.1055/s-0032-1306424     Document Type: Review

References (110)

1. Williams CD, Stengel J, Asike MI., et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology: 2011; 140 1 124 131
2. Bruix J, Sherman M.; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology: 2005; 42 5 1208 1236 (Pubitemid 43112690)
3. Blonski W, Kotlyar DS, Forde KA. Non-viral causes of hepatocellular carcinoma. World J Gastroenterol: 2010; 16 29 3603 3615
4. Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol: 2006; 40 Suppl 1 S5 S10 (Pubitemid 44309537)
5. Bosch FX, Ribes J, Diaz M, Clries R. Primary liver cancer: world-wide incidence and trends. Gastroenterology: 2004; 127 S3 S16
6. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med: 1999; 340 10 745 750 (Pubitemid 29114292)
7. Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD. Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol: 2008; 14 27 4300 4308
8. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology: 2010; 51 6 1972 1978
9. O'Leary JG, Landaverde C, Jennings L, Goldstein RM, Davis GL. Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants. Clin Gastroenterol Hepatol: 2011; 9 8 700 704, e1
10. Lok AS, Seeff LB, Morgan TR., et al. HALT-C Trial Group. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology: 2009; 136 1 138 148
11. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology: 2010; 51 5 1820 1832
12. Kawada N, Imanaka K, Kawaguchi T., et al. Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis. J Gastroenterol: 2009; 44 12 1190 1194
13. Hashimoto E, Yatsuji S, Tobari M., et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol: 2009; 44 Suppl 19 89 95
14. Chagas AL, Kikuchi LO, Oliveira CP., et al. Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients? Braz J Med Biol Res: 2009; 42 10 958 962
15. Ertle J, Dechne A, Sowa JP., et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer: 2011; 128 10 2436 2443
16. Paradis V, Zalinski S, Chelbi E., et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology: 2009; 49 3 851 859
17. Yasui K, Hashimoto E, Komorizono Y., et al. Japan NASH Study Group, Ministry of Health, Labour, and Welfare of Japan. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol: 2011; 9 5 428 433, quiz e50
18. Takuma Y, Nouso K. Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review. World J Gastroenterol: 2010; 16 12 1436 1441
19. Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM. Obesity and hepatocellular carcinoma. Gastroenterology: 2004; 127 5, Suppl 1 S97 S103 (Pubitemid 39423375)
20. Wolk A, Gridley G, Svensson M., et al. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control: 2001; 12 1 13 21 (Pubitemid 32125897)
21. Nair S, Mason A, Eason J, Loss G, Perrillo RP. Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology: 2002; 36 1 150 155 (Pubitemid 34700772)
22. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med: 2003; 348 17 1625 1638 (Pubitemid 36459468)
23. Mller H, Mellemgaard A, Lindvig K, Olsen JH. Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer: 1994; 30A 3 344 350 (Pubitemid 24152476)
24. Oh SW, Yoon YS, Shin SA. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J Clin Oncol: 2005; 23 21 4742 4754 (Pubitemid 46224078)
25. Chen CL, Yang HI, Yang WS., et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology: 2008; 135 1 111 121
26. Adami HO, Chow WH, Nyrn O., et al. Excess risk of primary liver cancer in patients with diabetes mellitus. J Natl Cancer Inst: 1996; 88 20 1472 1477
27. Wideroff L, Gridley G, Mellemkjaer L., et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst: 1997; 89 18 1360 1365 (Pubitemid 27418027)
28. Lagiou P, Kuper H, Stuver SO, Tzonou A, Trichopoulos D, Adami HO. Role of diabetes mellitus in the etiology of hepatocellular carcinoma. J Natl Cancer Inst: 2000; 92 13 1096 1099 (Pubitemid 30616486)
29. El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol: 2006; 4 3 369 380 (Pubitemid 43343895)
30. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology: 2004; 126 2 460 468 (Pubitemid 38182303)
31. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology: 2010; 51 6 1972 1978
32. George DK, Goldwurm S, MacDonald GA., et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology: 1998; 114 2 311 318 (Pubitemid 28093538)
33. Sorrentino P, D'Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione R. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol: 2009; 50 2 351 357
34. Mendler MH, Turlin B, Moirand R., et al. Insulin resistance-associated hepatic iron overload. Gastroenterology: 1999; 117 5 1155 1163 (Pubitemid 29512675)
35. Fujita N, Miyachi H, Tanaka H., et al. Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis. Cancer Epidemiol Biomarkers Prev: 2009; 18 2 424 432
36. Mnguez B, Tovar V, Chiang D, Villanueva A, Llovet JM. Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol: 2009; 25 3 186 194
37. Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis: 2007; 27 1 55 76
38. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology: 2008; 48 4 1312 1327
39. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell: 2004; 116 2 281 297
40. Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology: 2011; 53 5 1752 1763
41. Amir M, Czaja MJ. Autophagy in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol: 2011; 5 2 159 166
42. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology: 2010; 52 5 1836 1846
43. Hashimoto E, Tokushige K. Hepatocellular carcinoma in non-alcoholic steatohepatitis: Growing evidence of an epidemic? Hepatol Res: 2012; 42 1 1 14
44. Wang Y, Ausman LM, Greenberg AS, Russell RM, Wang XD. Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine-initiated early hepatocarcinogenesis in rats. Int J Cancer: 2009; 124 3 540 546
45. Park EJ, Lee JH, Yu GY., et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell: 2010; 140 2 197 208
46. Roderburg C, Trautwein C. Obesity and liver cancer: a key role for interleukin-6 and signal transducer and activator of transcription 3? Hepatology: 2010; 51 5 1850 1852
47. Bettermann K, Vucur M, Haybaeck J., et al. TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell: 2010; 17 5 481 496
48. Sun B, Karin M. Obesity, inflammation, and liver cancer. J Hepatol: 2011;; In press
49. Bougoulia M, Triantos A, Koliakos G. Effect of weight loss with or without orlistat treatment on adipocytokines, inflammation, and oxidative markers in obese women. Hormones (Athens): 2006; 5 4 259 269
50. Gannag-Yared MH, Khalife S, Semaan M, Fares F, Jambart S, Halaby G. Serum adiponectin and leptin levels in relation to the metabolic syndrome, androgenic profile and somatotropic axis in healthy non-diabetic elderly men. Eur J Endocrinol: 2006; 155 1 167 176 (Pubitemid 44103386)
51. Asano T, Watanabe K, Kubota N., et al. Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis. J Gastroenterol Hepatol: 2009; 24 10 1669 1676
52. Kamada Y, Matsumoto H, Tamura S., et al. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol: 2007; 47 4 556 564 (Pubitemid 47331742)
53. Brkenhielm E, Veitonmäki N, Cao R., et al. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A: 2004; 101 8 2476 2481 (Pubitemid 38269336)
54. Tsochatzis EA, Papatheodoridis GV, Archimandritis AJ. Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy. Mediators Inflamm: 2009; 2009 831670
55. Ikejima K, Honda H, Yoshikawa M., et al. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology: 2001; 34 2 288 297 (Pubitemid 32702342)
56. Marra F. Leptin and liver fibrosis: a matter of fat. Gastroenterology: 2002; 122 1399 1410
57. Ish-Shalom D, Christoffersen CT, Vorwerk P., et al. Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetologia: 1997; 40 Suppl 2 S25 S31 (Pubitemid 27306919)
58. Buzzelli G, Dattolo P, Pinzani M, Brocchi A, Romano S, Gentilini P. Circulating growth hormone and insulin-like growth factor-I in nonalcoholic liver cirrhosis with or without superimposed hepatocarcinoma: evidence of an altered circadian rhythm. Am J Gastroenterol: 1993; 88 10 1744 1748 (Pubitemid 23298126)
59. Price JA, Kovach SJ, Johnson T., et al. Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma. Hepatology: 2002; 36 5 1089 1097 (Pubitemid 35253424)
60. Tanaka S, Mohr L, Schmidt EV, Sugimachi K, Wands JR. Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes. Hepatology: 1997; 26 3 598 604 (Pubitemid 27392349)
61. Aleem E, Nehrbass D, Klimek F, Mayer D, Bannasch P. Upregulation of the insulin receptor and type I insulin-like growth factor receptor are early events in hepatocarcinogenesis. Toxicol Pathol: 2011; 39 3 524 543
62. Longato L, de la Monte S, Kuzushita N., et al. Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver. Hepatology: 2009; 49 6 1935 1943
63. Longato L, de la Monte S, Califano S, Wands JR. Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liver. Hepatol Res: 2008; 38 9 940 953
64. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell: 2002; 109 Suppl S81 S96
65. Luedde T, Schwabe RF. NF-B in the liverlinking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol: 2011; 8 2 108 118
66. Chiang SH, Bazuine M, Lumeng CN., et al. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell: 2009; 138 5 961 975
67. Sass G, Klinger N, Sirma H., et al. Inhibition of experimental HCC growth in mice by use of the kinase inhibitor DMAT. Int J Oncol: 2011; 39 2 433 442
68. Wree A, Kahraman A, Gerken G, Canbay A. Obesity affects the liver - the link between adipocytes and hepatocytes. Digestion: 2011; 83 1-2 124 133
69. Feldstein AE, Canbay A, Angulo P., et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology: 2003; 125 2 437 443 (Pubitemid 36929425)
70. Cho H, Black SC, Looper D., et al. Pharmacological characterization of a small molecule inhibitor of c-Jun kinase. Am J Physiol Endocrinol Metab: 2008; 295 5 E1142 E1151
71. Solinas G, Karin M. JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction. FASEB J: 2010; 24 8 2596 2611
72. Ferreira DM, Castro RE, Machado MV., et al. Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease. Diabetologia: 2011; 54 7 1788 1798
73. Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology: 2009; 49 1 87 96
74. Schattenberg JM, Singh R, Wang Y., et al. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology: 2006; 43 1 163 172 (Pubitemid 43733603)
75. Aghazadeh S, Yazdanparast R. Inhibition of JNK along with activation of ERK1/2 MAPK pathways improve steatohepatitis among the rats. Clin Nutr: 2010; 29 3 381 385
76. Maeda S. NF-B, JNK, and TLR signaling pathways in hepatocarcinogenesis. Gastroenterol Res Pract: 2010; 2010 367694
77. Chang Q, Zhang Y, Beezhold KJ., et al. Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. J Hepatol: 2009; 50 2 323 333
78. Tarn C, Lee S, Hu Y, Ashendel C, Andrisani OM. Hepatitis B virus X protein differentially activates RAS-RAF-MAPK and JNK pathways in X-transforming versus non-transforming AML12 hepatocytes. J Biol Chem: 2001; 276 37 34671 34680
79. Sakurai T, Maeda S, Chang L, Karin M. Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A: 2006; 103 28 10544 10551 (Pubitemid 44078014)
80. Eferl R, Ricci R, Kenner L., et al. Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell: 2003; 112 2 181 192 (Pubitemid 36144108)
81. He G, Yu GY, Temkin V., et al. Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell: 2010; 17 3 286 297
82. Wu WY, Li J, Wu ZS, Zhang CL, Meng XL. STAT3 activation in monocytes accelerates liver cancer progression. BMC Cancer: 2011; 11 506
83. Gu FM, Li QL, Gao Q., et al. IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma. Mol Cancer: 2011; 10 1 150
84. Gu FM, Li QL, Gao Q., et al. Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3. World J Gastroenterol: 2011; 17 34 3922 3932
85. Mueller KM, Kornfeld JW, Friedbichler K., et al. Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice. Hepatology: 2011; 54 4 1398 1409
86. Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol: 2007; 8 10 774 785 (Pubitemid 47462132)
87. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell: 2003; 115 5 577 590 (Pubitemid 37506046)
88. Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci: 2009; 122 Pt 20 3589 3594
89. Lee JW, Park S, Takahashi Y, Wang HG. The association of AMPK with ULK1 regulates autophagy. PLoS ONE: 2010; 5 11 e15394
90. Sokollik C, Ang M, Jones N. Autophagy: a primer for the gastroenterologist/hepatologist. Can J Gastroenterol: 2011; 25 12 667 674
91. Singh R, Kaushik S, Wang Y., et al. Autophagy regulates lipid metabolism. Nature: 2009; 458 7242 1131 1135
92. Dikic I, Johansen T, Kirkin V. Selective autophagy in cancer development and therapy. Cancer Res: 2010; 70 9 3431 3434
93. Egan DF, Shackelford DB, Mihaylova MM., et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science: 2011; 331 6016 456 461
94. Chan EY. mTORC1 phosphorylates the ULK1-mAtg13-FIP200 autophagy regulatory complex. Sci Signal: 2009; 2 51
95. Takamura A, Komatsu M, Hara T., et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev: 2011; 25 8 795 800
96. Qu X, Yu J, Bhagat G., et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest: 2003; 112 12 1809 1820 (Pubitemid 38063704)
97. Ding ZB, Shi YH, Zhou J., et al. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res: 2008; 68 22 9167 9175
98. Takeuchi O, Akira S. Toll-like receptors; their physiological role and signal transduction system. Int Immunopharmacol: 2001; 1 4 625 635 (Pubitemid 32206524)
99. Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology: 2008; 48 1 322 335 (Pubitemid 351975556)
100. Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol: 2007; 47 4 571 579 (Pubitemid 47331747)
101. Honkakoski P, Zelko I, Sueyoshi T, Negishi M. The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol: 1998; 18 10 5652 5658 (Pubitemid 28450516)
102. Moreau A, Vilarem MJ, Maurel P, Pascussi JM. Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response. Mol Pharm: 2008; 5 1 35 41 (Pubitemid 351300032)
103. Huang W, Zhang J, Washington M., et al. Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol: 2005; 19 6 1646 1653 (Pubitemid 41002992)
104. Takizawa D, Kakizaki S, Horiguchi N, Yamazaki Y, Tojima H, Mori M. Constitutive active/androstane receptor promotes hepatocarcinogenesis in a mouse model of non-alcoholic steatohepatitis. Carcinogenesis: 2011; 32 4 576 583
105. Peyrou M, Bourgoin L, Foti M. PTEN in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and cancer. Dig Dis: 2010; 28 1 236 246
106. Anezaki Y, Ohshima S, Ishii H., et al. Sex difference in the liver of hepatocyte-specific Pten-deficient mice: A model of nonalcoholic steatohepatitis. Hepatol Res: 2009; 39 6 609 618
107. Sze KM, Wong KL, Chu GK, Lee JM, Yau TO, Oi-Lin Ng I. Loss of phosphatase and tensin homolog enhances cell invasion and migration through AKT/Sp-1 transcription factor/matrix metalloproteinase 2 activation in hepatocellular carcinoma and has clinicopathologic significance. Hepatology: 2011; 53 5 1558 1569
108. Mnguez B, Tovar V, Chiang D, Villanueva A, Llovet JM. Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol: 2009; 25 3 186 194
109. 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. Gastroenterology: 2007; 133 2 647 658 (Pubitemid 47187346)
110. Wang B, Majumder S, Nuovo G., et al. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology: 2009; 50 4 1152 1161