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The progression of liver fibrosis is related with overexpression of the miR-199 and 200 families.

Murakami Y, Toyoda H, Tanaka M, Kuroda M, Harada Y, Matsuda F, Tajima A, Kosaka N, Ochiya T, Shimotohno K - PLoS ONE (2011)

Bottom Line: Chronic hepatitis C (CH) can develop into liver cirrhosis (LC) and hepatocellular carcinoma (HCC).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.This information may uncover the critical mechanism of progression of liver fibrosis. miRNA expression profiling has potential for diagnostic and therapeutic applications.

View Article: PubMed Central - PubMed

Affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. ymurakami@genome.med.kyoto-u.ac.jp

ABSTRACT

Background: 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.

Methodology: 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.

Principle findings: 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.

Conclusion: 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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Liver fibrosis in human liver biopsy specimen.A. B. C. D. and E. miRNAs whose expression differs significantly between F0 and F3, F0 and F1, F0 and F2, F1 and F2, and F1 and F3, respectively. Relative expression level of each miRNA in human liver biopsy specimen by microarray. Data from microarray were also statistically analyzed using Welch's test and the Bonferroni correction for multiple hypotheses testing. Fold change, p-value are listed in Table S2.
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pone-0016081-g002: Liver fibrosis in human liver biopsy specimen.A. B. C. D. and E. miRNAs whose expression differs significantly between F0 and F3, F0 and F1, F0 and F2, F1 and F2, and F1 and F3, respectively. Relative expression level of each miRNA in human liver biopsy specimen by microarray. Data from microarray were also statistically analyzed using Welch's test and the Bonferroni correction for multiple hypotheses testing. Fold change, p-value are listed in Table S2.

Mentions: We then established human miRNAs expression profile by using 105 fresh-frozen human chronic hepatitis (CH) C liver tissues without a history of anti-viral therapy, classified according to the grade of the liver fibrosis (F0, F1, F2, and F3 referred to METAVIR fibrosis stages)(Figure 2, Table S2). Fibrosis grade F0 was considered to be the negative control because these samples were derived from patients with no finding of liver fibrosis. In zebrafish, most highly tissue-specific miRNAs are expressed during embryonic development; approximately 30% of all miRNAs are expressed at a given time point in a given tissue [13]. In mammals, the 20–30% miRNA call rate has recently been validated [14]. Such analysis revealed that the diversity of miRNA expression level among specimens was small. Therefore, we focused on miRNAs with a fold change in mean expression level greater than 1.5 (p<0.05) in the two arbitrary groups of liver fibrosis.


The progression of liver fibrosis is related with overexpression of the miR-199 and 200 families.

Murakami Y, Toyoda H, Tanaka M, Kuroda M, Harada Y, Matsuda F, Tajima A, Kosaka N, Ochiya T, Shimotohno K - PLoS ONE (2011)

Liver fibrosis in human liver biopsy specimen.A. B. C. D. and E. miRNAs whose expression differs significantly between F0 and F3, F0 and F1, F0 and F2, F1 and F2, and F1 and F3, respectively. Relative expression level of each miRNA in human liver biopsy specimen by microarray. Data from microarray were also statistically analyzed using Welch's test and the Bonferroni correction for multiple hypotheses testing. Fold change, p-value are listed in Table S2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3025920&req=5

pone-0016081-g002: Liver fibrosis in human liver biopsy specimen.A. B. C. D. and E. miRNAs whose expression differs significantly between F0 and F3, F0 and F1, F0 and F2, F1 and F2, and F1 and F3, respectively. Relative expression level of each miRNA in human liver biopsy specimen by microarray. Data from microarray were also statistically analyzed using Welch's test and the Bonferroni correction for multiple hypotheses testing. Fold change, p-value are listed in Table S2.
Mentions: We then established human miRNAs expression profile by using 105 fresh-frozen human chronic hepatitis (CH) C liver tissues without a history of anti-viral therapy, classified according to the grade of the liver fibrosis (F0, F1, F2, and F3 referred to METAVIR fibrosis stages)(Figure 2, Table S2). Fibrosis grade F0 was considered to be the negative control because these samples were derived from patients with no finding of liver fibrosis. In zebrafish, most highly tissue-specific miRNAs are expressed during embryonic development; approximately 30% of all miRNAs are expressed at a given time point in a given tissue [13]. In mammals, the 20–30% miRNA call rate has recently been validated [14]. Such analysis revealed that the diversity of miRNA expression level among specimens was small. Therefore, we focused on miRNAs with a fold change in mean expression level greater than 1.5 (p<0.05) in the two arbitrary groups of liver fibrosis.

Bottom Line: Chronic hepatitis C (CH) can develop into liver cirrhosis (LC) and hepatocellular carcinoma (HCC).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.This information may uncover the critical mechanism of progression of liver fibrosis. miRNA expression profiling has potential for diagnostic and therapeutic applications.

View Article: PubMed Central - PubMed

Affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. ymurakami@genome.med.kyoto-u.ac.jp

ABSTRACT

Background: 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.

Methodology: 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.

Principle findings: 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus