Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties

TY - JOUR

T1 - Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties

AU - Coulouarn, C

AU - Factor, V M

AU - Andersen, Jesper Bøje

AU - Durkin, M E

AU - Thorgeirsson, S S

PY - 2009/10/8

Y1 - 2009/10/8

N2 - Growing evidence indicates that microRNAs have a significant role in tumor development and may constitute robust biomarkers for cancer diagnosis and prognosis. In this study, we evaluated the clinical and functional relevance of microRNA-122 (miR-122) expression in human hepatocellular carcinoma (HCC). We report that miR-122 is specifically repressed in a subset of primary tumors that are characterized by poor prognosis. We further show that the loss of miR-122 expression in tumor cells segregates with specific gene expression profiles linked to cancer progression, namely the suppression of hepatic phenotype and the acquisition of invasive properties. We identify liver-enriched transcription factors as central regulatory molecules in the gene networks associated with loss of miR-122, and provide evidence suggesting that miR-122 is under the transcriptional control of HNF1A, HNF3A and HNF3B. We further show that loss of miR-122 results in an increase of cell migration and invasion and that restoration of miR-122 reverses this phenotype. In conclusion, miR-122 is a marker of hepatocyte-specific differentiation and an important determinant in the control of cell migration and invasion. From a clinical point of view, our study emphasizes miR-122 as a diagnostic and prognostic marker for HCC progression.

AB - Growing evidence indicates that microRNAs have a significant role in tumor development and may constitute robust biomarkers for cancer diagnosis and prognosis. In this study, we evaluated the clinical and functional relevance of microRNA-122 (miR-122) expression in human hepatocellular carcinoma (HCC). We report that miR-122 is specifically repressed in a subset of primary tumors that are characterized by poor prognosis. We further show that the loss of miR-122 expression in tumor cells segregates with specific gene expression profiles linked to cancer progression, namely the suppression of hepatic phenotype and the acquisition of invasive properties. We identify liver-enriched transcription factors as central regulatory molecules in the gene networks associated with loss of miR-122, and provide evidence suggesting that miR-122 is under the transcriptional control of HNF1A, HNF3A and HNF3B. We further show that loss of miR-122 results in an increase of cell migration and invasion and that restoration of miR-122 reverses this phenotype. In conclusion, miR-122 is a marker of hepatocyte-specific differentiation and an important determinant in the control of cell migration and invasion. From a clinical point of view, our study emphasizes miR-122 as a diagnostic and prognostic marker for HCC progression.

KW - Carcinoma, Hepatocellular

KW - Cell Line, Tumor

KW - Gene Expression Profiling

KW - Humans

KW - Liver Neoplasms

KW - MicroRNAs

KW - Neoplasm Invasiveness

KW - Neoplasm Metastasis

KW - Phenotype

KW - Prognosis

U2 - 10.1038/onc.2009.211

DO - 10.1038/onc.2009.211

M3 - Journal article

C2 - 19617899

SN - 0950-9232

VL - 28

SP - 3526

EP - 3536

JO - Oncogene

JF - Oncogene

IS - 40

ER -