Identification of miRNA-7 by genome-wide analysis as a critical sensitizer for TRAIL-induced apoptosis in glioblastoma cells

• Xiao Zhang ^[1] ; Xiang Zhang ^[1] ; Shijie Hu ^[1] ; Minhua Zheng ^[1] ; Jie Zhang ^[1] ; Jianhui Zhao ^[1] ; Xiaofang Zhang ^[1] ; Bo Yan ^[1] ; Lintao Jia ^[1] ; Jing Zhao ^[1] ; Kaichun Wu ^[2] ; Angang Yang ^[1] ; Rui Zhang ^[1]
  1. [1] Fourth Military Medical University

     Fourth Military Medical University

     China

     
  2. [2] The State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi 710032, P.R. China
• Localización: Nucleic acids research, ISSN 0305-1048, Vol. 45, Nº. 10, 2017, págs. 5930-5944
• Idioma: inglés
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• Resumen

  • Glioblastoma (GBM) is still one of the most lethal forms of brain tumor despite of the improvements in treatments. TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. To define the novel pathways that regulate susceptibility to TRAIL in GBM cells, we performed a genome-wide expression profiling of microRNAs in GBM cell lines with the distinct sensitivity to TRAIL-induced apoptosis. We found that the expression pattern of miR-7 is closely correlated with sensitivity of GBM cells to TRAIL. Furthermore, our gain and loss of function experiments showed that miR-7 is a potential sensitizer for TRAIL-induced apoptosis in GBM cells. In the mechanistic study, we identified XIAP is a direct downstream gene of miR-7. Additionally, this regulatory axis could also exert in other types of tumor cells like hepatocellular carcinoma cells. More importantly, in the xenograft model, enforced expression of miR-7 in TRAIL-overexpressed mesenchymal stem cells increased apoptosis and suppressed tumor growth in an exosome dependent manner. In conclusion, we identify that miR-7 is a critical sensitizer for TRAIL-induced apoptosis, thus making it as a promising therapeutic candidate for TRAIL resistance in GBM cells.