MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer.
Journal: 2007/September - Gastroenterology
ISSN: 0016-5085
Abstract:
OBJECTIVE
microRNAs (miRNAs) are short noncoding RNAs that regulate gene expression negatively. Although a role for aberrant miRNA expression in cancer has been postulated, the pathophysiologic role and relevance of aberrantly expressed miRNA to tumor biology has not been established.
METHODS
We evaluated the expression of miRNA in human hepatocellular cancer (HCC) by expression profiling, and defined a target gene and biologically functional effect of an up-regulated miRNA.
RESULTS
miR-21 was noted to be highly overexpressed in HCC tumors and cell lines in expression profiling studies using a miRNA microarray. Inhibition of miR-21 in cultured HCC cells increased expression of the phosphatase and tensin homolog (PTEN) tumor suppressor, and decreased tumor cell proliferation, migration, and invasion. In contrast-enhanced miR-21 expression by transfection with precursor miR-21 increased tumor cell proliferation, migration, and invasion. Moreover, an increase in cell migration was observed in normal human hepatocytes transfected with precursor miR-21. PTEN was shown to be a direct target of miR-21, and to contribute to miR-21 effects on cell invasion. Modulation of miR-21 altered focal adhesion kinase phosphorylation and expression of matrix metalloproteases 2 and 9, both downstream mediators of PTEN involved in cell migration and invasion.
CONCLUSIONS
Aberrant expression of miR-21 can contribute to HCC growth and spread by modulating PTEN expression and PTEN-dependent pathways involved in mediating phenotypic characteristics of cancer cells such as cell growth, migration, and invasion.
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Gastroenterology 133(2): 647-658

MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer

Department of Internal Medicine, Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas
Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, Ohio
Department of Molecular and Cellular Biochemistry, College of Medicine, Ohio State University, Columbus, Ohio
Address requests for reprints to: Tushar Patel, MBChB, The Ohio State University Medical Center, N2 Doan Hall, 410 West 10th Avenue, Columbus, Ohio 43210

Abstract

Background & Aims

microRNAs (miRNAs) are short noncoding RNAs that regulate gene expression negatively. Although a role for aberrant miRNA expression in cancer has been postulated, the pathophysiologic role and relevance of aberrantly expressed miRNA to tumor biology has not been established.

Methods

We evaluated the expression of miRNA in human hepatocellular cancer (HCC) by expression profiling, and defined a target gene and biologically functional effect of an up-regulated miRNA.

Results

miR-21 was noted to be highly overexpressed in HCC tumors and cell lines in expression profiling studies using a miRNA microarray. Inhibition of miR-21 in cultured HCC cells increased expression of the phosphatase and tensin homolog (PTEN) tumor suppressor, and decreased tumor cell proliferation, migration, and invasion. In contrast-enhanced miR-21 expression by transfection with precursor miR-21 increased tumor cell proliferation, migration, and invasion. Moreover, an increase in cell migration was observed in normal human hepatocytes transfected with precursor miR-21. PTEN was shown to be a direct target of miR-21, and to contribute to miR-21 effects on cell invasion. Modulation of miR-21 altered focal adhesion kinase phosphorylation and expression of matrix metalloproteases 2 and 9, both downstream mediators of PTEN involved in cell migration and invasion.

Conclusions

Aberrant expression of miR-21 can contribute to HCC growth and spread by modulating PTEN expression and PTEN-dependent pathways involved in mediating phenotypic characteristics of cancer cells such as cell growth, migration, and invasion.

Abstract

Hepatocellular cancer (HCC) is the most common malignancy of the liver, and is the fifth most common cause of cancer worldwide. The incidence of HCC has been increasing in the United States in recent years.1 Although the risk factors for HCC are well characterized, the molecular pathogenesis of these tumors is understood poorly.2 An improved understanding of critical pathways involved in cancer cell development and progression will facilitate the development of effective targeted therapeutic strategies for HCC.

Tissue invasion and metastases are key phenotypic characteristics of cancer cells.3 These processes require that cancer cells acquire the ability to proliferate in an unrestricted manner, as well as to migrate and invade adjacent tissues. Tumor growth and metastases can be facilitated by genetic changes in cancer cells that regulate these phenotypic changes. Many recent studies have described genetic changes occurring in experimental and clinical hepatocarcinogenesis. Moreover, gene expression patterns have been shown to be valuable in predicting survival as well as response to therapy.4 These studies have been helpful in identifying potential candidates for therapeutic intervention.

microRNAs (miRNAs) are a class of gene products that recently were implicated in several cancers.57 Several hundred miRNAs have been described in human beings. miRNAs can function as potent regulators of gene expression and altered miRNA levels can result in aberrant expression of gene products that may contribute to cancer biology. In many studies, the expression of miRNAs appears to be lower in malignant tissues compared with the corresponding nonmalignant tissues. However, the expression of selected miRNAs can be increased. Altered expression of several miRNAs has been described in HCC.8,9 However, the specific role of aberrantly expressed miRNAs is unknown. We postulated that aberrantly expressed miRNAs may contribute to tumor growth and spread by modulating the expression of gene products involved in phenotypic characteristics of cancer cells such as cell growth, migration, and invasion.

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