406943

MIR152

MIRN152;microRNA 152;MIR152;microRNA 152

hsa-mir-152

17q21.32

ncRNA

The hepatitis B virus (HBV) X protein has been implicated as a potential trigger of the epigenetic modifications of some genes during hepatocarcinogenesis, but the underlying mechanisms remain unknown. microRNAs (miRNAs), which are noncoding RNAs that regulate gene expression, are involved in diverse biological functions and in carcinogenesis. In this study, we investigated whether some miRNAs are aberrantly expressed and involved in the regulation of the abnormal DNA methylation status in HBV-related hepatocellular carcinoma (HCC). Our results showed that the expression of microRNA-152 (miR-152) was frequently down-regulated in HBV-related HCC tissues in comparison with adjacent noncancerous hepatic tissues and was inversely correlated to DNA methyltransferase 1 (DNMT1) messenger RNA (mRNA) expression in HBV-related HCCs. The forced expression of miR-152 in liver cell lines resulted in a marked reduction of the expression of DNMT1 at both the mRNA and protein levels by directly targeting the 3 untranslated regions of DNMT1. This in turn led to a decrease in global DNA methylation, whereas inhibition of miR-152 caused global DNA hypermethylation and increased the methylation levels of two tumor suppressor genes, glutathione S-transferase pi 1 (GSTP1) and E-cadherin 1 (CDH1). CONCLUSION: Our findings suggest that miR-152 is frequently down-regulated and regulates DNMT1 in HBV-related HCC. These findings support a tumor-suppressive role of miR-152 in the epigenetic aberration of HBV-related HCC and the potential development of miRNA-based targeted approaches for the treatment of HBV-related HCC.

Dysregulation of microRNAs is a common feature in human cancers, including breast cancer (BC). Here we describe the epigenetic regulation of miR-148a and miR-152 and their impact on BC cells. Due to the hypermethylation of CpG island, the expression levels of both miR-148a and miR-152 (miR-148a/152) are decreased in BC tissues and cells. DNMT1, the DNA methyltransferase 1 for the maintenance methylation, is aberrantly up-regulated in BC and its overexpression is responsible for hypermethylation of miR-148a and miR-152 promoters. Intriguingly, we found that DNMT1 expression, which is one of the targets of miR-148a/152, is inversely correlated with the expression levels of miR-148a/152 in BC tissues. Those results lead us to propose a negative feedback regulatory loop between miR-148a/152 and DNMT1 in BC. More importantly, we demonstrate that IGF-IR and IRS1, often overexpressed in BC, are two novel targets of miR-148a/152. Overexpression of miR-148a or miR-152 significantly inhibits BC cell proliferation, colony formation, and tumor angiogenesis via targeting IGF-IR and IRS1 and suppressing their downstream AKT and MAPK/ERK signaling pathways. Our results suggest a novel miR-148a/152-DNMT1 regulatory circuit and reveal that miR-148a and miR-152 act as tumor suppressors by targeting IGF-IR and IRS1, and that restoration of miR-148a/152 expression may provide a strategy for therapeutic application to treat BC patients.

BACKGROUND: microRNAs (miRNAs) are a class of short non-coding RNAs that function in diverse biological processes. Aberrant miR-152 expression has been frequently reported in various malignant tumors. However, the mechanism of miR-152 in prostate cancer (PCa) remains unclear. This study aims to determine the function of miR-152 in PCa cells and identify the novel molecular targets regulated by miR-152. METHODS: The expression levels of transforming growth factor-alpha (TGFalpha) were determined in three samples of PCa and adjacent non-tumorous tissues by Western blot analysis. miR-152 levels in 48 primary PCa and 15 non-malignant tissue samples were measured by qRT-PCR. The effects of forced miR-152 expression or TGFalpha knockdown on PCa cells were evaluated by cell migration and invasion assays, as well as Western blot analysis. Dual-luciferase reporter assay was used to identify binding sites between miR-152 and TGFalpha 3-UTR. RESULTS: TGFalpha was upregulated in PCa tissue samples compared with that in adjacent normal ones. miR-152 expression was significantly decreased in primary PCa samples compared with that in non-malignant samples. Patients with Gleason scores >7 exhibited lower miR-152 levels than those with lower scores. Moreover, low miR-152 expression is correlated with advanced pathological T-stages. Forced miR-152 expression or TGFalpha knockdown significantly reduced the migratory and invasive capabilities of PCa cells in vitro. TGFalpha is a direct target gene of miR-152. CONCLUSIONS: Our findings suggest that miR-152 can act as a tumor suppressor that targets TGFalpha. miR-152 is a promising molecular target that inhibits PCa cell migration and invasion.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Great interest persists in useful therapeutic targets in GBM. Aberrant expression of long non-coding RNAs (lncRNAs) has been functionally associated with many cancers. Here, we elucidated the function and the possible molecular mechanisms of lncRNA XIST in human glioblastoma stem cells (GSCs). Our results proved that XIST expression was up-regulated in glioma tissues and GSCs. Functionally, knockdown of XIST exerted tumor-suppressive functions by reducing cell proliferation, migration and invasion as well as inducing apoptosis. The in vivo studies also showed that knockdown of XIST suppressed tumor growth and produced high survival in nude mice. Further, there was reciprocal repression between XIST and miR-152. Mechanistic investigations defined the direct binding ability of the predicted miR-152 binding site on the XIST. In addition, XIST and miR-152 are probably in the same RNA induced silencing complex (RISC). Finally, miR-152 mediated the tumor-suppressive effects that knockdown of XIST exerted. Taken together, these results provided a comprehensive analysis of XIST in GSCs and important clues for understanding the key roles of lncRNA-miRNA functional network in human glioma.