非酒精性脂肪性肝病相关肝细胞癌发病机制研究进展

doi:10.3969/j.issn.1672-5069.2019.03.036

摘要/Abstract

摘要： 非酒精性脂肪性肝病（NAFLD）是目前临床上最常见的慢性肝病之一,NAFLD相关肝细胞癌（NAFLD-HCC）的发病率也逐年上升。众多因素参与了NAFLD-HCC的发生发展,但其具体的发病机制还不清楚。本文重点介绍近年有关其发病机制的研究进展。

关键词: 肝细胞癌, 非酒精性脂肪性肝病, 发病机制

Abstract: Non-alcoholic fatty liver disease （NAFLD） is currently one of the most common chronic liver diseases worldwide，and the incidence of NAFLD-related hepatocellular carcinoma （NAFLD-HCC） increases recently. Many factors are involved in the pathogenesis of NAFLD-HCC， but the specific mechanism remains unclear. This review summarizes recent research findings about the carcinogenesis of NAFLD-HCC.

Key words: Hepatocellular carcinoma, Non-alcoholic fatty liver disease, Carcinogenesis

朱光曦（综述）, 文良志, 陈东风（审校）. 非酒精性脂肪性肝病相关肝细胞癌发病机制研究进展[J]. 实用肝脏病杂志, 2019, 22(3): 453-456.

Zhu Guangxi，Wen Liangzhi，Chen Dongfeng. Pathogenesis of non-alcoholic fatty liver disease-related hepatocellular carcinoma[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2019, 22(3): 453-456.

参考文献

[1] Starley BQ,Calcagno CJ,Harrison SA.Nonalcoholic fatty liver disease and hepatocellular carcinoma:a weighty connection. Hepatology,2010,51(5):1820-1832.
[2] Younossi ZM,Koenig AB, Abdelatif D, et al.Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence,incidence,and outcomes. Hepatology,2016,64(1):73-84.
[3] El-Serag HB,Rudolph KL.Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology,2007,132(7):2557-2576.
[4] Younossi ZM,Otgonsuren M,Henry L,et al.Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology,2015,62(6):1723-1730.
[5] Wong RJ,Aguilar M,Cheung R,et al.Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology,2015,148(3):547-555.
[6] Gastaldelli A. Insulin resistance and reduced metabolic flexibility:cause or consequence of NAFLD Clin Sci,2017,131(22):2701-2704.
[7] Pasarín M,Abraldes JG,Liguori E,et al.Intrahepatic vascular changes in non-alcoholic fatty liver disease:Potential role of insulin-resistance and endothelial dysfunction. World J Gastroenterol,2017,23(37):6777-6787.
[8] Baffy G.Hepatocellular carcinoma in non-alcoholic fatty liver disease:Epidemiology,pathogenesis,and prevention. J Clin Transl Hepatol,2013,1(2):131-137.
[9] Miquilena-Colina ME,Lima-Cabello E,Sánchez-Campos S,et al.Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance,hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut,2011,60(10):1394-1402.
[10] Hassan MM,Curley SA,Li D,et al.Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer,2010,116(8):1938-1946.
[11] Liu W,Baker SS,Baker RD,et al.Antioxidant mechanisms in nonalcoholic fatty liver disease. Curr Drug Targets,2015,16(12):1301-1314.
[12] Ma C,Kesarwala AH,Eggert T,et al.NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature,2016,531(7593):253-257.
[13] Gentric G,Maillet V,Paradis V.et al.Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest,2015,125(3):981-992.
[14] Tanaka S,Miyanishi K,Kobune M,et al.Increased hepatic oxidative DNA damage in patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. J Gastroenterol,2013,48(11):1249-1258.
[15] Motoshima H,Goldstein BJ,Igata M,et al.AMPK and cell proliferation-AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol,2006,574(Pt 1):63-71.
[16] Smith BK,Marcinko K,Desjardins EM, et al.Treatment of nonalcoholic fatty liver disease:role of AMPK. Am J Physiol Endocrinol Metab,2016,311(4):E730-E740.
[17] Zheng L,Yang W,Wu F,et al.Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clin Cancer Res,2013,19(19):5372-5380.
[18] He C,Klionsky DJ.Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet,2009,43:67-93.
[19] Parzych KR,Klionsky DJ.An overview of autophagy:morphology,mechanism,and regulation. Antioxid Redox Signal,2014,20(3):460-473.
[20] Dash S,Chava S,Chandra PK,et al.Autophagy in hepatocellular carcinomas:from pathophysiology to therapeutic response. Hepat Med,2016,8:9-20.
[21] Lin CW,Zhang H,Li M,et al.Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J Hepatol,2013,58(5):993-999.
[22] Wang Z,Han W,Sui X,et al.Autophagy:A novel therapeutic target for hepatocarcinoma(Review). Oncol Lett,2014,7(5):1345-1351.
[23] Kotsafti A,Farinati F,Cardin R,et al.Autophagy and apoptosis-related genes in chronic liver disease and hepatocellular carcinoma. BMC Gastroenterol,2012,12:118.
[24] Singh SS,Vats S,Chia AY,et al.Dual role of autophagy in hallmarks of cancer. Oncogene,2018,37(9):1142-1158.
[25] Vander Heiden MG,Cantley LC,Thompson CB.Understanding the Warburg effect:The metabolic requirements of cell proliferation. Science,2009,324(5930):1029-1033.
[26] Beyoglu D,Idle JR.Idle. The metabolomic window into hepatobiliary disease. J Hepatol,2013,59(4):842-858.
[27] Teilhet C,Morvan D,Joubert-Zakeyh J,et al. Specificities of human hepatocellular carcinoma developed on non-alcoholic fatty liver disease in absence of cirrhosis revealed by tissue extracts (1)H-NMR spectroscopy. Metabolites,2017,7(4).pii:E49.
[28] Xu G,Ye J,Liu XJ,et al.Activation of pluripotent genes in hepatic progenitor cells in the transition of nonalcoholic steatohepatitis to pre-malignant lesions. Lab Invest,2017,97(10):1201-1217.
[29] Qin J,Li R,Raes J.A human gut microbial gene catalogue established by metagenomic sequencing. Nature,2010,464(7285):59-65.
[30] Miele L,Valenza V,La Torre G,et al.Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology,2009,49(6):1877-1887.
[31] Boursier J,Diehl AM.Implication of gut microbiota in nonalcoholic fatty liver disease. PLOS Pathogens,2015,11(1):e1004559.
[32] Shen F,Zheng RD,Sun XQ,et al.Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease. Hepatobiliary Pancreat Dis Int,2017,16(4):375-381.
[33] Loo TM,Kamachi F,Watanabe Y,et al.Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov,2017,7(5):522-538.
[34] Kaelin WG Jr,McKnight SL. Influence of metabolism on epigenetics and disease. Cell,2013,153(1):56-69.
[35] Tian Y,Wong VW,Wong GL,et al.Histone deacetylase HDAC8 promotes insulin resistance and beta-catenin activation in NAFLD-associated hepatocellular carcinoma. Cancer Res,2015,75(22):4803-4816.
[36] de Conti A,Dreval K,Tryndyak V,et al. Inhibition of the cell death pathway in nonalcoholic steatohepatitis (NASH)-related hepatocarcinogenesis is associated with histone H4 lysine 16 deacetylation. Mol Cancer Res,2017,15(9):1163-1172.
[37] Zhang T,Kho DH,Wang Y,et al.Gp78,an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer. PLoS One,2015,10(3):e0118448.