microRNA-125a reduces proliferation and invasion of oral squamous cell carcinoma cells by targeting estrogen-related receptor alpha: implications for cancer therapeutics [Gene Regulation]

September 29th, 2014 by Tiwari, A., Shivananda, S., Gopinath, K. S., Kumar, A.

ESRRA functions as a transcription factor and regulates the expression of several genes, such as WNT11 and OPN. Upregulation of ESRRA has been reported in several cancers. However, the mechanism underlying its upregulation is unclear. Further, the reports regarding the role and regulation of ESRRA in oral squamous cell carcinoma (OSCC) are completely lacking. Here we show that tumor suppressor miR-125a directly binds to the 3′UTR of ESRRA and represses its expression. Overexpression of miR-125a in OSCC cells drastically reduced the level of ESRRA, decreased cell proliferation and increased apoptosis. Conversely, the delivery of a miR-125a inhibitor to these cells drastically increased the level of ESRRA, increased cell proliferation and decreased apoptosis. miR-125a-mediated downregulation of ESRRA impaired anchorage-independent colony formation and invasion of OSCC cells. Reduced cell proliferation and increased apoptosis of OSCC cells were dependent on the presence of the 3′UTR in ESRRA. The delivery of a miR-125a mimic to OSCC cells resulted in marked regression of xenografts in nude mice. Whereas, the delivery of a miR-125a inhibitor to OSCC cells resulted in a significant increase of xenografts and abrogated the tumor suppressor function of miR-125a. We observed an inverse correlation between expression levels of miR-125a and ESRRA in OSCC samples. In summary, upregulation of ESRRA due to downregulation of miR-125a is not only a novel mechanism for its upregulation in OSCC, but decreasing the level of ESRRA by using a synthetic miR-125a mimic may have an important role in therapeutic intervention of OSCC and other cancers.
  • Posted in Journal of Biological Chemistry, Publications
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