miR-152 Is a Tumor Suppressor microRNA That Is Silenced by DNA Hypermethylation in Endometrial Cancer

Abstract

The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer. Cancer Res; 71(20); 6450-62. Ó2011 AACR.

A microRNA-152 that targets the phosphatase and tensin homolog to inhibit low oxygen induced-apoptosis in human brain microvascular endothelial cells

“…The authors of one report have suggested that miR-152 acts as a tumor suppressor in prostate cancer by targeting the 3'UTR of TGF-α (Zhu et al, 2013). Other researchers reported epigenetic silencing by DNA hypermethylation of miR-152 in endometrial cancer, and restoration of miR-152 expression in endometrial cancer cell lines resulted in inhibition of tumor cell growth, both in vitro and in vivo (Tsuruta et al, 2011). However, in our study, we found that miR-152 could be induced by hypoxia and inhibited hypoxia-induced apoptosis in vascular endothelial cells.…”

Overexpression of Rictor protein in colorectal cancer is correlated with tumor progression and prognosis

“…The ILK-Rictor complex acts as a potential molecular target for preventing/reversing fibrosis caused by EMT, cancer progression and metastasis (13). Tsuruta et al observed that Rictor, as a target gene of miR-152, participated in regulating the proliferation of cancer cells in endometrial carcinoma (10). Therefore, it was hypothesized that Rictor protein may be involved in the proliferation, migration and invasion of CRC.…”

“…Currently, only a limited number of reports indicate that Rictor has certain biological functions in malignant tumors. For example, it has been reported that microRNA (miR)-152 acts as a tumor suppressor by targeting Rictor in gynecological cancers (10). Although Rictor may be involved in cancer progression, its expression in CRC remains unclear.…”

How Micrornas Affect the Expression of Human Leukocyte Antigeng in Pregnancy

“…miR-152 is located within an intron of COPZ2 and therefore it can be thought that this miRNA can be simultaneously expressed with the COPZ2 transcript. Indeed, it was found that the expression of these two transcripts are similar in human endometrial cancer cell lines (Tsuruta et al, 2011). Therefore it can be suggested that miR-152 is regulated via the intronic pathway.…”