Elevated Expression of the miR-17–92 Polycistron and miR-21 in Hepadnavirus-Associated Hepatocellular Carcinoma Contributes to the Malignant Phenotype

Abstract

Alterations in microRNA (miRNA) expression in both human and animal models have been linked to many forms of cancer. Such miRNAs, which act directly as repressors of gene expression, have been found to frequently reside in fragile sites and genomic regions associated with cancer. This study describes a miRNA signature for human primary hepatitis B virus-positive human hepatocellular carcinoma. Moreover, two known oncomiRs-miRNAs with known roles in cancer-the miR-17-92 polycistron and miR-21, exhibited increased expression in 100% of primary human and woodchuck hepatocellular carcinomas surveyed. To determine the importance of these miRNAs in tumorigenesis, an in vitro antisense oligonucleotide knockdown model was evaluated for its ability to reverse the malignant phenotype. Both in human and woodchuck HCC cell lines, separate treatments with antisense oligonucleotides specific for either the miR-17-92 polycistron (all six members) or miR-21 caused a 50% reduction in both hepatocyte proliferation and anchorage-independent growth. The combination of assays presented here supports a role for these miRNAs in the maintenance of the malignant transformation of hepatocytes.

Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen

“…An emerging body of evidence suggests that miRNAs are often overexpressed or downregulated in a number of human malignancies, and these genes are thought to function as tumor suppressors or oncogenes (Ambros, 2004). Recent studies demonstrate that various viruses, including human T-cell leukemia virus type 1 and Epstein-Barr virus, disturb the physiological functions of host cells by altering cellular miRNAs expression, leading to changes in cell proliferation or to a malignant phenotype (Connolly et al, 2008;Godshalk et al, 2008;Pichler et al, 2008;Tomita et al, 2009). Based on these observations, we speculate that particular genes targeted by miRNA might be involved in the process of SV40 ST-induced cell transformation.…”

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…Tomimaru et al (2010) have demonstrated that miR-21 has an effect in the modulation of the response to IFN-␣/5-FU favoring the clinical response and survival. This miRNA is the first to be studied as a therapeutic tool and other two studies (Connolly et al, 2008;Zhu et al, 2011) have shown that the transfection of tumor cells with antisense oligonucleotides specific for mir-21 leads to a reduction of the cell growth and survival. Likewise studies by Xu et al (2011a), Bihrer et al (2011), Marquez et al (2010 have shown that serum levels of miR-21 are increased with a progressive course from chronic hepatitis to cirrhosis and hepatocellular carcinoma.…”

Overexpression of miR-21 Promotes an In vitro Metastatic Phenotype by Targeting the Tumor Suppressor RHOB

“…We previously showed that miR-21 is overexpressed in both primary HCC (11) and HCC cell lines (12). Increased miR-21 expression has also been reported in a wide range of tumor types (6,(12)(13)(14).…”