miR-92a Inhibits Peritoneal Dissemination of Ovarian Cancer Cells by Inhibiting Integrin α5 Expression
miR-92a Inhibits Peritoneal Dissemination of Ovarian Cancer Cells by Inhibiting Integrin α5 Expression
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DOI：
10.1016/j.ajpath.2013.01.039
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发表时间：
2013-05-01
影响因子：
6
通讯作者：
Kimura, Tadashi
中科院分区：
文献类型：
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作者：
Ohyagi-Hara, Chifumi;Sawada, Kenjiro;Kimura, Tadashi
卵巢癌的特点是广泛腹膜播散和腹水，治愈率仅为30%。正如之前报道的，整合素α5在卵巢癌的腹膜播散中发挥着关键作用。我们的目标是鉴定一种调节整合素 α 5 表达的新 miRNA，并分析靶向该 miRNA 的治疗潜力。通过 IHC 分析，我们证明整合素 α5 的高表达与国际妇产科联合会 III 期卵巢癌日本患者的不良预后相关。基于 miRNA 算法搜索，我们将 hsa-mir-92a (miR-92a) 确定为候选者。各种癌细胞中miR-92a的表达水平与ITGA5的表达显着负相关。转染前体miR-92a可降低卵巢癌细胞中整合素α5的表达，同时抑制癌细胞粘附、侵袭和增殖。 miR-92a 过表达降低了 ITGA5 3'-非翻译区的荧光素酶活性，表明 ITGA5 mRNA 是 miR-92a 的直接靶标。在体内卵巢癌异种移植物中，HeyA-8 细胞中 miR-92a 的强制表达抑制了腹膜播散。尽管将有效且无毒的基于 miRNA 的癌症疗法引入临床还有很长的路要走，但通过靶向 miR-92a 抑制整合素 α 5 表达仍需要进一步探索，以用于未来在卵巢癌治疗中的应用。
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.