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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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The relationship between expression level of miR-199 and 200 families and expression level of three fibrosis related genes.A. Administration of TGFβ in LX2 cells showed that the expression level of three fibrosis related genes were higher than that in non-treated cells. The data shown are the means+SD of three independent experiments. Asterisk was indicated to the significant difference of p<0.05 (two-tailed Student-t test). B. The expression levels of 3 fibrosis related genes in LX2 cells with overexpressing miR-199a, 199a*, 200a, or 200b, respectively were significantly higher than that in cells transfected with control miRNA (p<0.05; two-tailed Student t-test).
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pone-0016081-g004: The relationship between expression level of miR-199 and 200 families and expression level of three fibrosis related genes.A. Administration of TGFβ in LX2 cells showed that the expression level of three fibrosis related genes were higher than that in non-treated cells. The data shown are the means+SD of three independent experiments. Asterisk was indicated to the significant difference of p<0.05 (two-tailed Student-t test). B. The expression levels of 3 fibrosis related genes in LX2 cells with overexpressing miR-199a, 199a*, 200a, or 200b, respectively were significantly higher than that in cells transfected with control miRNA (p<0.05; two-tailed Student t-test).

Mentions: In order to reveal the function of miR-199a, miR-199a*, miR-200a, and miR-200b, we investigated the involvement of these miRNAs in the modulation of fibrosis-related gene in LX-2 cells. The endogenous expression level of these 4 miRNAs in LX2 and normal liver was low according to the microarray study (Figure S2). Transforming growth factor (TGF)β is one of the critical factors for the activation of HSC during chronic inflammation [15] and TGFβ strongly induced expression of three fibrosis-related genes include a matrix degrading complex comprised of α1 procollagen, matrix remodeling complex, comprised of metalloproteinases-13 (MMP-13), tissue inhibitors of metalloproteinases-1 (TIMP-1) in LX-2 cells (Figure 4A). Furthermore, overexpression of miR-199a, miR-199a*, miR-200a and miR-200b in LX-2 cells resulted significant induction of above fibrosis-related genes compared with control miRNA (Figure 4B). Finally we validated the involvement of TGFβ in the modulation of these miRNAs. In LX-2 cells treated with TGFβ, the expression levels of miR-199a and miR-199a* were significantly higher than in untreated cells; the expression levels of miR-200a and miR-200b were significantly lower than in untreated cells. Thus, our in vitro analysis suggested a possible involvement of miR-199a, 199a*, 200a, and 200b in the progression 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)

The relationship between expression level of miR-199 and 200 families and expression level of three fibrosis related genes.A. Administration of TGFβ in LX2 cells showed that the expression level of three fibrosis related genes were higher than that in non-treated cells. The data shown are the means+SD of three independent experiments. Asterisk was indicated to the significant difference of p<0.05 (two-tailed Student-t test). B. The expression levels of 3 fibrosis related genes in LX2 cells with overexpressing miR-199a, 199a*, 200a, or 200b, respectively were significantly higher than that in cells transfected with control miRNA (p<0.05; two-tailed Student t-test).
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Related In: Results  -  Collection

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

pone-0016081-g004: The relationship between expression level of miR-199 and 200 families and expression level of three fibrosis related genes.A. Administration of TGFβ in LX2 cells showed that the expression level of three fibrosis related genes were higher than that in non-treated cells. The data shown are the means+SD of three independent experiments. Asterisk was indicated to the significant difference of p<0.05 (two-tailed Student-t test). B. The expression levels of 3 fibrosis related genes in LX2 cells with overexpressing miR-199a, 199a*, 200a, or 200b, respectively were significantly higher than that in cells transfected with control miRNA (p<0.05; two-tailed Student t-test).
Mentions: In order to reveal the function of miR-199a, miR-199a*, miR-200a, and miR-200b, we investigated the involvement of these miRNAs in the modulation of fibrosis-related gene in LX-2 cells. The endogenous expression level of these 4 miRNAs in LX2 and normal liver was low according to the microarray study (Figure S2). Transforming growth factor (TGF)β is one of the critical factors for the activation of HSC during chronic inflammation [15] and TGFβ strongly induced expression of three fibrosis-related genes include a matrix degrading complex comprised of α1 procollagen, matrix remodeling complex, comprised of metalloproteinases-13 (MMP-13), tissue inhibitors of metalloproteinases-1 (TIMP-1) in LX-2 cells (Figure 4A). Furthermore, overexpression of miR-199a, miR-199a*, miR-200a and miR-200b in LX-2 cells resulted significant induction of above fibrosis-related genes compared with control miRNA (Figure 4B). Finally we validated the involvement of TGFβ in the modulation of these miRNAs. In LX-2 cells treated with TGFβ, the expression levels of miR-199a and miR-199a* were significantly higher than in untreated cells; the expression levels of miR-200a and miR-200b were significantly lower than in untreated cells. Thus, our in vitro analysis suggested a possible involvement of miR-199a, 199a*, 200a, and 200b in the progression 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