Cyclin G1 Is a Target of miR-122a, a MicroRNA Frequently Down-regulated in Human Hepatocellular Carcinoma

Laura Gramantieri,Carlo M Croce,Luigi Bolondi,George A Calin,Eros Ferrazzi,Manuela Ferracin,Francesca Fornari,Massimo Negrini,Gian Luca Grazi,Catia Giovannini,Angelo Veronese,Chang-Gong Liu,Silvia Sabbioni

doi:10.1158/0008-5472.can-06-4607

Abstract

We investigated the role of microRNAs (miRNAs) in the pathogenesis of human hepatocellular carcinoma (HCC). A genome-wide miRNA microarray was used to identify differentially expressed miRNAs in HCCs arisen on cirrhotic livers. Thirty-five miRNAs were identified. Several of these miRNAs were previously found deregulated in other human cancers, such as members of the let-7 family, mir-221, and mir-145. In addition, the hepato-specific miR-122a was found down-regulated in approximately 70% of HCCs and in all HCC-derived cell lines. Microarray data for let-7a, mir-221, and mir-122a were validated by Northern blot and real-time PCR analysis. Understanding the contribution of deregulated miRNAs to cancer requires the identification of gene targets. Here, we show that miR-122a can modulate cyclin G1 expression in HCC-derived cell lines and an inverse correlation between miR-122a and cyclin G1 expression exists in primary liver carcinomas. These results indicate that cyclin G1 is a target of miR-122a and expand our knowledge of the molecular alterations involved in HCC pathogenesis and of the role of miRNAs in human cancer.

Highlights

Hepatocellular carcinoma (HCC) accounts for 80% to 90% of liver cancers and it is one of the most prevalent carcinomas throughout the world [1]
To identify the miRNAs that are differentially expressed between cirrhosis and HCC, we did a statistical comparison between the two groups of samples
Thirty-five miRNAs emerged as differentially regulated in HCC tissue with respect to cirrhosis (Table 2)

Summary

Introduction

Hepatocellular carcinoma (HCC) accounts for 80% to 90% of liver cancers and it is one of the most prevalent carcinomas throughout the world [1]. Cirrhosis represents the strongest predisposing factor, as 80% of HCCs develop in cirrhotic livers [2]. By assaying HCCs with DNA microarrays, several signaling pathways potentially involved in HCC development and progression through the modulation of multiple mRNAs have been recognized [3]. Deregulated expression of protein involved in cell cycle regulation and in DNA repair has extensively been described as a crucial event in the carcinogenetic process leading to HCC development [6]. A new class of small noncoding RNAs, microRNAs (miRNA), has been discovered in animals and plants [7,8,9]. MiRNAs are 19- to 25-nucleotide-long RNAs, able to bind A new class of small noncoding RNAs, microRNAs (miRNA), has been discovered in animals and plants [7,8,9]. miRNAs are 19- to 25-nucleotide-long RNAs, able to bind

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Conclusion