title: Differentially expressed MicroRNAs provide mechanistic insight into fibrosis-associated liver carcinogenesis in mice.
abstract: Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers, with a rising incidence worldwide. The molecular mechanisms associated with the development of HCC are complex and include multiple interconnected molecular alterations with mounting evidence indicating an important role of microRNAs (miRNAs) in the pathogenesis of HCC. In humans, the development of HCC is commonly associated with liver cirrhosis. To study fibrosis-associated liver carcinogenesis, we used a mouse model designed to emulate the development of HCC in cirrhotic liver. Specifically, we were interested in evaluating the role of miRNAs in the molecular pathogenesis of liver carcinogenesis in male B6C3F1/J mice treated with N-nitrosodiethylamine (DEN) or carbon tetrachloride (CCl4 ) alone or a combination of DEN and CCl4 and characterized by a differential tumor incidence that increased in the following order: DEN<CCl4 <DEN+CCl4 . Treatment with DEN alone had negligible effect on hepatic miRNA expression. In contrast, treatment with either CCl4 alone or a combination of DEN and CCl4 resulted in major changes in miRNA expression. The analysis of miRNA profiles demonstrated an involvement of dysregulated miRNAs in major processes associated with the development of liver tumors, including inflammation, fibrosis, and stem cell activation. Importantly, the greatest incidence of liver tumors in mice treated with DEN+CCl4 was accompanied by a distinct over-expression of miRNAs suggesting that miRNA alterations may be responsible, at least in part, for the high tumor incidence.
authors: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas.
authors: April K
authors: AK
authors: Marrone
authors: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas.
authors: Svitlana
authors: S
authors: Shpyleva
authors: College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.
authors: Grace
authors: G
authors: Chappell
authors: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas.
authors: Volodymyr
authors: V
authors: Tryndyak
authors: College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.
authors: Takeki
authors: T
authors: Uehara
authors: First Department of Surgery, University of Yamanashi, Chuo, Japan.
authors: Masato
authors: M
authors: Tsuchiya
authors: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas.
authors: Frederick A
authors: FA
authors: Beland
authors: College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.
authors: Ivan
authors: I
authors: Rusyn
authors: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas.
authors: Igor P
authors: IP
authors: Pogribny
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D045744:Cell Line, Tumor; D004052:Diethylnitrosamine / Q000633:toxicity; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D004052:Diethylnitrosamine; D002251:Carbon Tetrachloride
keywords: hepatocellular carcinoma; liver carcinogenesis; microRNAs; mouse