MicroRNA expression analysis in high fat diet-induced NAFLD-NASH-HCC progression: study on C57BL/6J mice

BMC Cancer

Research Article

Valentina Mastroiaco¹  Roberta Sferra¹  Daniela Verzella¹  Alessandra Tessitore¹  Daria Capece¹  Filippo Del Vecchio¹  Francesca Zazzeroni¹  Germana Cicciarelli¹  Agata Gaggiano¹  Edoardo Alesse¹  Mariafausta Fischietti¹  Antonella Vetuschi¹  Remo Barnabei² 

[1] Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, via Vetoio - Coppito 2, 67100, L’Aquila, Italy;S. Salvatore Hospital, Unit of Laboratory Medicine, L’Aquila, Italy;

关键词: microRNA;    NAFLD;    NASH;    HCC;    High fat diet;    Low fat diet;   

DOI  :  10.1186/s12885-015-2007-1

 received in 2015-08-17, accepted in 2015-12-14,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundHepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Non-alcoholic fatty liver disease (NAFLD) is a frequent chronic liver disorder in developed countries. NAFLD can progress through the more severe non alcoholic steatohepatitis (NASH), cirrhosis and, lastly, HCC. Genetic and epigenetic alterations of coding genes as well as deregulation of microRNAs (miRNAs) activity play a role in HCC development. In this study, the C57BL/6J mouse model was long term high-fat (HF) or low-fat (LF) diet fed, in order to analyze molecular mechanisms responsible for the hepatic damage progression.MethodsMice were HF or LF diet fed for different time points, then plasma and hepatic tissues were collected. Histological and clinical chemistry assays were performed to assess the progression of liver disease. MicroRNAs’ differential expression was evaluated on pooled RNAs from tissues, and some miRNAs showing dysregulation were further analyzed at the individual level.ResultsCholesterol, low and high density lipoproteins, triglycerides and alanine aminotransferase increase was detected in HF mice. Gross anatomical examination revealed hepatomegaly in HF livers, and histological analysis highlighted different degrees and levels of steatosis, inflammatory infiltrate and fibrosis in HF and LF animals, demonstrating the progression from NAFLD through NASH. Macroscopic nodules, showing typical neoplastic features, were observed in 20 % of HF diet fed mice. Fifteen miRNAs differentially expressed in HF with respect to LF hepatic tissues during the progression of liver damage, and in tumors with respect to HF non tumor liver specimens were identified. Among them, miR-340-5p, miR-484, miR-574-3p, miR-720, whose expression was never described in NAFLD, NASH and HCC tissues, and miR-125a-5p and miR-182, which showed early and significant dysregulation in the sequential hepatic damage process.ConclusionsIn this study, fifteen microRNAs which were modulated in hepatic tissues and in tumors during the transition NAFLD-NASH-HCC are reported. Besides some already described, new and early dysregulated miRNAs were identified. Functional analyses are needed to validate the results here obtained, and to better define the role of these molecules in the progression of the hepatic disease.

【 授权许可】

CC BY   
© Tessitore et al. 2015