The Tumor Suppressive MicroRNAmiR-218Targets the mTOR ComponentRictorand Inhibits AKT Phosphorylation in Oral Cancer

Abstract

The incidence of oral squamous cell carcinoma (OSCC) is rising rapidly in developed countries, posing a growing challenge due to the poor management of this type of malignancy at present. In this study, we profiled tumor suppressive microRNAs (miRNAs) that are silenced by DNA hypermethylation in OSCC using a functionbased screening approach. This approach employed a cell proliferation assay for 327 synthetic miRNAs in two OSCC cell lines. Among the 110 miRNAs identified in this set that exhibited inhibitory properties, we compared DNA methylation and expression status in a wider panel of OSCC cell lines and primary tumor tissues, resulting in the identification of miR-218 and miR-585 as functionally significant miRNA genes that are frequently silenced in OSCC by DNA hypermethylation. Ectopic expression of miR-218 and miR-585 in OSCC cells lacking endogenous expression reduced cell growth in part through caspase-mediated apoptosis. Notably, miR-218 reduced levels of the rapamycin-insensitive component of mTOR, Rictor, in a manner associated with a suppression of Akt S473 phosphorylation. Together our findings define miR-585 as a tumor suppressive function that is often epigenetically silenced in OSCC, and they identify Rictor as a novel target of miR-218, suggesting that activation of the mTOR-Akt signaling pathway induced by Rictor contributes centrally to oral carcinogenesis. Cancer Res; 71(17); 5765-78. Ó2011 AACR.

MicroRNA-218 inhibits melanogenesis by directly suppressing microphthalmia-associated transcription factor expression

“…[22][23][24][25] In our study, a novel function and mechanism of miR-218 was found in its targeting of Mitf 3'-UTR and suppression of melanogenesis in a normal melanocyte model of murine melan-a cells. 26 A luciferase activity assay demonstrated the direct binding of miR-218 to the 3'-UTR of the Mitf gene (Fig.…”

Learning regulatory programs by threshold SVD regression

“…The only miRNA that showed high expression in proliferative subtype and low expression in immunoreactive subtype is miR-218. However, recent studies suggested its role as a tumor suppressor and inhibiting cell proliferation (12,13). This suggested the complexities of miRNA regulations in different cancer types.…”

Reduced miRNA-218 expression in pancreatic cancer patients as a predictor of poor prognosis

“…Recent studies have demonstrated that miR-218 is downregulated in various types of cancer, including cervical cancer, gastric cancer, lung cancer, colon cancer, prostate cancer, and bladder cancer (Davidson et al, 2010;Song et al, 2010;Tie et al, 2010;Leite et al, 2011;Uesugi et al, 2011;Li et al, 2012a;Li et al, 2012b;Chiyomaru et al, 2012;He et al, 2012). However, the level of miR0218 expression, and its clinical significance in pancreatic cancer, remains to be investigated.…”

“…miR-218 functions as a tumor suppressor gene in various types of cancer, targeting multiple genes and regulating biological processes (Song et al, 2010;Tie et al, 2010;Uesugi et al, 2011;He et al, 2012;Li et al, 2012b;Yamamoto et al, 2013). Overexpression of miR-218 is known to inhibit cancer cell proliferation, invasion, and metastasis, and promote cancer cell apoptosis.…”

“…microRNA-218 (miR-218) is a vertebrate-specific miRNA that has been predicted and experimentally confirmed to play a crucial role in tumorigenesis and tumor progression by regulating the expression of potential targets (Hassan et al, 2012). Recent studies have indicated that miR-218 is down-regulated in various types of cancer, including cervical cancer, gastric cancer, lung cancer, colon cancer, prostate cancer, and bladder cancer (Davidson et al, 2010;Song et al, 2010;Tie et al, 2010;Uesugi et al, 2011;Leite et al, 2011;Li et al, 2012a,b;Chiyomaru et al, 2012;He et al, 2012). However, the level of expression of miR-218 and its clinical significance in pancreatic cancer has not been investigated.…”