Abstract
microRNAs (miRNAs) are short noncoding RNAs that negatively regulate gene expression. Although recent evidences have been indicated that their aberrant expression may play an important role in cancer stem cells, the mechanism of their deregulation in neoplastic transformation of liver cancer stem cells (LCSCs) has not been explored. In our study, the HCC model was established in F344 rats by DEN induction. The EpCAM(+) cells were sorted out from unfractionated fetal liver cells and liver cancer cells using the FACS analysis and miRNA expression profiles of two groups were screened through microarray platform. Gain-of-function studies were performed in vitro and in vivo to determine the role of miR-92b on proliferation and differentiation of the hepatic progenitors. In addition, luciferase reporter system and gene function analysis were used to predict miR-92b target. we found that miR-92b was highly downregulated in EpCAM(+) fetal liver cells in expression profiling studies. RT-PCR analysis demonstrated reverse correlation between miR-92b expression and differentiation degree in human HCC samples. Overexpression of miR-92b in EpCAM(+) fetal liver cells significantly increased proliferation and inhibited differentiation as well as in vitro and in vivo studies. Moreover, we verified that C/EBPß is a direct target of miR-92b and contributes to its effects on proliferation and differentiation. We conclude that aberrant expression of miR-92b can result in proliferation increase and differentiation arrest of hepatic progenitors by targeting C/EBPß.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism*
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CCAAT-Enhancer-Binding Protein-beta / genetics
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CCAAT-Enhancer-Binding Protein-beta / metabolism*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology*
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism*
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Cell Proliferation
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Cells, Cultured
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Epithelial Cell Adhesion Molecule
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Fetus / cytology
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Fetus / metabolism*
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Gene Expression Profiling
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Hepatocytes / cytology
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Hepatocytes / metabolism*
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Humans
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Male
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Oligonucleotide Array Sequence Analysis
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Rats
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Rats, Inbred F344
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Reverse Transcriptase Polymerase Chain Reaction
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Up-Regulation
Substances
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Antigens, Neoplasm
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CCAAT-Enhancer-Binding Protein-beta
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Cell Adhesion Molecules
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Epithelial Cell Adhesion Molecule
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MIRN92 microRNA, human
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MicroRNAs
Grants and funding
The study was supported by the supported by the Scientific Supporting Funds of PLA General Hospital (2012FC-CXYY-4008), Postdoctoral Science Foundation (2012M521875 and 2012M521864), National Natural Science Foundation of China (81200324), and Bureau of Health Medical Scientific Research Foundation of Hainan Province (Qiongwei 2012 PT-70). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.