The Progression of Liver Fibrosis Is Related with Overexpression of the miR-199 and 200 Families

Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
PLoS ONE (Impact Factor: 3.23). 01/2011; 6(1):e16081. DOI: 10.1371/journal.pone.0016081
Source: PubMed


Chronic hepatitis C (CH) can develop into liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Liver fibrosis and HCC development are strongly correlated, but there is no effective treatment against fibrosis because the critical mechanism of progression of liver fibrosis is not fully understood. microRNAs (miRNAs) are now essential to the molecular mechanisms of several biological processes. In order to clarify how the aberrant expression of miRNAs participates in development of the liver fibrosis, we analyzed the liver fibrosis in mouse liver fibrosis model and human clinical samples.
In a CCL(4)-induced mouse liver fibrosis model, we compared the miRNA expression profile from CCL(4) and olive oil administrated liver specimens on 4, 6, and 8 weeks. We also measured expression profiles of human miRNAs in the liver biopsy specimens from 105 CH type C patients without a history of anti-viral therapy.
Eleven mouse miRNAs were significantly elevated in progressed liver fibrosis relative to control. By using a large amount of human material in CH analysis, we determined the miRNA expression pattern according to the grade of liver fibrosis. We detected several human miRNAs whose expression levels were correlated with the degree of progression of liver fibrosis. In both the mouse and human studies, the expression levels of miR-199a, 199a*, 200a, and 200b were positively and significantly correlated to the progressed liver fibrosis. The expression level of fibrosis related genes in hepatic stellate cells (HSC), were significantly increased by overexpression of these miRNAs.
Four miRNAs are tightly related to the grade of liver fibrosis in both human and mouse was shown. This information may uncover the critical mechanism of progression of liver fibrosis. miRNA expression profiling has potential for diagnostic and therapeutic applications.

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Available from: Atsushi Tajima
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    • "The role of miRNAs that seems to be emerging in innate and adaptive immunity provides a strong indication of an association with the regulation of inflammatory diseases (5). In order to understand the critical pathways of HSC activation, recent studies performed comprehensive comparative bioinformatics analysis of microarrays of quiescent and activated HSC, and they identified 12 up-regulated miRNAs (miR-874, -290, -501,-349, -325-sp, -328, -138, -143, -207, -87, -140, -193) and nine downregulated miRNAs (miR-341, -206-3p, -156, -16, -375, -122, -146a, -29b, -126) (6,8,12). These studies suggested that the altered miRNA patterns that occur after chronic liver disease have a significant effect on the progression of fibrosis. "

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    • "ZEB1 and ZEB2, the transcriptional repressors of E-cadherin are influenced by members of the miRNA-200 family and lead to epithelial to mesenchymal transition [125] [126]. Upregulation of miRNAs miR-200a and miR-200b in liver fibrosis is consistent with their influence in this disease mechanism [127]. A role in regulating the PTEN -TGF-beta axis was ascribed to a network of miRNAs (including miR-106a, miR-106b, miR-18a, miR-18b, and others) that results in EMT of hepatocytes thus suggesting potential for this miRNA network to promote neoplastic transformation of hepatocytes [128]. "
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    • "Similar findings were also obtained in diverse strains of mice fed a choline- and folate-deficient diet [45]; in this work, circulating levels of a group of miRNAs, including miR-200b, significantly correlated with severity of NAFLD-specific liver damage, thus representing highly sensitive plasma biomarkers that allow noninvasive monitoring of the progression and extent of NAFLD-related liver injury. In the study of Murakami et al. [72], in both mouse models and human clinical specimens of liver fibrosis, the expression of 11 miRNAs was related to the progression of the disease; notably, the upregulation of four miRNAs, miR-199a, -199a*, -200a, and -200b, positively and significantly correlated with the grade of fibrosis. Furthermore, their overexpression in HSCs significantly increased the level of fibrosis-related genes. "
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