Alcoholic hepatitis accelerates early hepatobiliary cancer by increasing stemness and miR-122-mediated HIF-1α activation

被引:72
作者
Ambade, Aditya [1 ]
Satishchandran, Abhishek [1 ]
Szabo, Gyongyi [1 ]
机构
[1] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01604 USA
关键词
EPITHELIAL-MESENCHYMAL TRANSITION; HEPATOCELLULAR-CARCINOMA; LIVER-CANCER; CIRCULATING MICRORNAS; RISK-FACTORS; MOUSE MODEL; CELLS; MIR-122; HYPOXIA; DISEASE;
D O I
10.1038/srep21340
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Alcohol-related hepatocellular carcinoma (HCC) develops with advanced alcoholic liver disease and liver fibrosis. Using adult mice, we evaluate the effect of alcoholic steatohepatitis on early hepatobiliary carcinoma after initiation by diethyl-nitrosamine (DEN). Here we show that alcohol-fed DEN-injected mice have higher ALT and liver-to-body weight ratio compared to pair-fed DEN-injected mice. Alcohol feeding results in steatohepatitis indicated by increased pro-inflammatory cytokines and fibrotic genes. MRI and liver histology of alcohol+DEN mice shows hepatobiliary cysts, early hepatic neoplasia and increase in serum alpha-fetoprotein. Proliferation makers (BrdU, cyclin D1, p53) and cancer stem cell markers (CD133 and nanog) are significantly up-regulated in livers of alcohol-fed DEN-injected mice compared to controls. In livers with tumors, loss of miR-122 expression with a significant up-regulation of miR-122 target HIF-1 alpha is seen. We conclude that alcoholic steatohepatitis accelerates hepatobiliary tumors with characteristic molecular features of HCC by up-regulating inflammation, cell proliferation, stemness, and miR-122 loss.
引用
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页数:15
相关论文
共 64 条
[1]   Cellular aspects of alpha-fetoprotein reexpression in tumors [J].
Abelev, GI ;
Eraiser, TL .
SEMINARS IN CANCER BIOLOGY, 1999, 9 (02) :95-107
[2]   Changing Hepatocellular Carcinoma Incidence and Liver Cancer Mortality Rates in the United States [J].
Altekruse, Sean F. ;
Henley, S. Jane ;
Cucinelli, James E. ;
McGlynn, Katherine A. .
AMERICAN JOURNAL OF GASTROENTEROLOGY, 2014, 109 (04) :542-553
[3]  
[Anonymous], 2015, CANC FACTS FIG 2015
[4]   MicroRNA-122 Inhibits Tumorigenic Properties of Hepatocellular Carcinoma Cells and Sensitizes These Cells to Sorafenib [J].
Bai, Shoumei ;
Nasser, Mohd W. ;
Wang, Bo ;
Hsu, Shu-Hao ;
Datta, Jharna ;
Kutay, Huban ;
Yadav, Arti ;
Nuovo, Gerard ;
Kumar, Pawan ;
Ghoshal, Kalpana .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (46) :32015-32027
[5]   Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases [J].
Bala, Shashi ;
Petrasek, Jan ;
Mundkur, Shiv ;
Catalano, Donna ;
Levin, Ivan ;
Ward, Jeanine ;
Alao, Hawau ;
Kodys, Karen ;
Szabo, Gyongyi .
HEPATOLOGY, 2012, 56 (05) :1946-1957
[6]   Rodent models of alcoholic liver disease: Of mice and men [J].
Brandon-Warner, Elizabeth ;
Schrum, Laura W. ;
Schmidt, C. Max ;
McKillop, Iain H. .
ALCOHOL, 2012, 46 (08) :715-725
[7]   Chronic Ethanol Feeding Accelerates Hepatocellular Carcinoma Progression in a Sex-Dependent Manner in a Mouse Model of Hepatocarcinogenesis [J].
Brandon-Warner, Elizabeth ;
Walling, Tracy L. ;
Schrum, Laura W. ;
McKillop, Iain H. .
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, 2012, 36 (04) :641-653
[8]   MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches [J].
Callegari, E. ;
Gramantieri, L. ;
Domenicali, M. ;
D'Abundo, L. ;
Sabbioni, S. ;
Negrini, M. .
CELL DEATH AND DIFFERENTIATION, 2015, 22 (01) :46-57
[9]   Mature hepatocytes exhibit unexpected plasticity by direct dedifferentiation into liver progenitor cells in culture [J].
Chen, Yixin ;
Wong, Philip P. ;
Sjeklocha, Lucas ;
Steer, Clifford J. ;
Sahin, M. Behnan .
HEPATOLOGY, 2012, 55 (02) :563-574
[10]   Oxidation of Methyl and Ethyl Nitrosamines by Cytochrome P450 2E1 and 2B1 [J].
Chowdhury, Goutam ;
Calcutt, M. Wade ;
Nagy, Leslie D. ;
Guengerich, F. Peter .
BIOCHEMISTRY, 2012, 51 (50) :9995-10007