The tumor suppressive microRNA miR-218 targets the mTOR component rictor and inhibits AKT phosphorylation in oral cancer

Atsushi Uesugi, Ken Ichi Kozaki, Tomohiko Tsuruta, Mayuko Furuta, Kei Ichi Morita, Issei Imoto, Ken Omura, Johji Inazawa

Research output: Contribution to journalArticle

195 Citations (Scopus)

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 function-based 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.

Original languageEnglish
Pages (from-to)5765-5778
Number of pages14
JournalCancer Research
Volume71
Issue number17
DOIs
Publication statusPublished - Sep 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Uesugi, A., Kozaki, K. I., Tsuruta, T., Furuta, M., Morita, K. I., Imoto, I., Omura, K., & Inazawa, J. (2011). The tumor suppressive microRNA miR-218 targets the mTOR component rictor and inhibits AKT phosphorylation in oral cancer. Cancer Research, 71(17), 5765-5778. https://doi.org/10.1158/0008-5472.CAN-11-0368