Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 182, Issue 5, Pages 1876-1889Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2013.01.039
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [21791555, 23592447, 22390308, 24249080]
- Uehara Memorial Foundation
- Kanae Foundation for the Promotion of Medical Science
- Sagawa Foundation for Promotion of Cancer Research
- Grants-in-Aid for Scientific Research [24590459, 23592447, 23890102, 21791555, 23592443, 24659723, 25293342, 22390308] Funding Source: KAKEN
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Ovarian cancer is characterized by widespread peritoneal dissemination and ascites and has a cure rate of only 30%. As has been previously reported, integrin alpha 5 plays a key role in the peritoneal dissemination of ovarian cancer. Our aim was to identify a new miRNA that regulates integrin alpha 5 expression and analyze the therapeutic potential of targeting this miRNA. By using an IHC analysis, we proved that high integrin alpha 5 expression correlates with a poor prognosis in Japanese patients with International Federation of Gynecology and Obstetrics stage III ovarian cancer. Based on an miRNA algorithm search, we identified hsa-mir-92a (miR-92a) as a candidate. The level of miR-92a expression was significantly inversely correlated with ITGA5 expression in various cancer cells. Transfection of precursor miR-92a reduced integrin alpha 5 expression in ovarian cancer cells, which was accompanied by the inhibition of cancer cell adhesion, invasion, and proliferation. miR-92a overexpression reduced the luciferase activity of the ITGA5 3'-untranslated region, suggesting that ITGA5 mRNA is a direct target of miR-92a. In in vivo ovarian cancer xenografts, the enforced expression of miR-92a in HeyA-8 cells suppressed peritoneal dissemination. Although we still have a long way to go before an effective and nontoxic miRNA-based cancer therapy can be introduced into the clinic, the inhibition of integrin alpha 5 expression by targeting miR-92a needs to be explored further for future applications in ovarian cancer treatment.
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