miR-92a Inhibits Peritoneal Dissemination of Ovarian Cancer Cells by Inhibiting Integrin α5 Expression

• Published in: The American journal of pathology Vol. 182; no. 5; pp. 1876 - 1889
• Main Authors: Ohyagi-Hara, Chifumi, Sawada, Kenjiro, Kamiura, Shoji, Tomita, Yasuhiko, Isobe, Aki, Hashimoto, Kae, Kinose, Yasuto, Mabuchi, Seiji, Hisamatsu, Takeshi, Takahashi, Toshifumi, Kumasawa, Keiichi, Nagata, Shigenori, Morishige, Ken-ichirou, Lengyel, Ernst, Kurachi, Hirohisa, Kimura, Tadashi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2013
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Base Sequence; Biomarkers, Tumor - metabolism; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Integrin alpha5 - genetics; Integrin alpha5 - metabolism; Mice; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Molecular Sequence Data; Neoplasm Invasiveness; Neoplasm Staging; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Pathology; Peritoneal Neoplasms - pathology; Peritoneal Neoplasms - secondary; Prognosis; Protein Binding - genetics; Xenograft Model Antitumor Assays; Young Adult
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2013.01.039

Ovarian cancer is characterized by widespread peritoneal dissemination and ascites and has a cure rate of only 30%. As has been previously reported, integrin α5 plays a key role in the peritoneal dissemination of ovarian cancer. Our aim was to identify a new miRNA that regulates integrin α5 expression and analyze the therapeutic potential of targeting this miRNA. By using an IHC analysis, we proved that high integrin α5 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 α5 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 α5 expression by targeting miR-92a needs to be explored further for future applications in ovarian cancer treatment.