Abstract 3097: microRNA-21 inhibitor potentiates anti-tumor effect of radiation therapy in vitro and in vivo.

Abstract

Abstract microRNA-21 (miR-21) plays significant roles in carcinogenesis and is highly expressed in diverse human cancers. In this study, we evaluated the potential of targeting miRNA-21 to overcome the radioresistance of human cancer cells having an activated PI3K-Akt signaling and also aimed to elucidate the mechanisms of radiosensitization, and the effect on epithelial- mesenchymal transition (EMT). A panel of human cancer cells (U251, U87, A549, MDA-MB-468, SKBR-3 cells) were transfected with miR-21 led to up-regulation of PI3K-Akt signaling and increased radioresistance compared with the cancer cells that were treated with nonspecific control. In contrast, a specific inhibitor of miR-21, an antipeptide nucleic acid (PNA) attenuated PI3K-Akt signaling and radiosensitized a panel of human cancer cells we tested. Inhibition of miR-21 was associated with persistent γH2AX foci formation and down-regulation of p-DNA-PKcs. While ectopic overexpression of miR-21 exhibited higher invasion and migration potential and increased vascular tube formation, inhibitor of miR-21 decreased these typical features of EMT. Treatment of anti-miR-21 significantly decreased tumor burden in nude mice bearing intracranial U251 xenografts compared to control as measured by bioluminescence. Combined treatment of anti-miR-21 and radiation further decreased tumor burden compared to each treatment alone. In summary, miR-21 is an important onco-miR which confers radioresistance and diverse features of EMT. Inhibition of miR-21 could be a potential strategy for improving the efficacy of radiation therapy via unique modulation of PI3K-Akt signaling and EMT. Citation Format: Bong Jun Cho, Eun Jung Choi, Hans H. Kim, David J. Lee, Sun Ha Chun, In-Ah Kim. microRNA-21 inhibitor potentiates anti-tumor effect of radiation therapy in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3097. doi:10.1158/1538-7445.AM2013-3097