Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR-193a-5p and regulating mTOR expression
| Autor: | Fang Shen, Xianmei Huang, Chunming Jiang, Jianmin Du, Xiaoli Li, Xiao-Hua Wang, Xiang Fang, Zhangli Liu, Jin Su |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell Survival Down-Regulation Apoptosis 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Line Tumor Glioma Autophagy Temozolomide medicine Humans Viability assay Antineoplastic Agents Alkylating PI3K/AKT/mTOR pathway Pharmacology Brain Neoplasms Chemistry TOR Serine-Threonine Kinases Tumor Suppressor Proteins General Medicine medicine.disease Up-Regulation Cell biology Dacarbazine Gene Expression Regulation Neoplastic MicroRNAs 030104 developmental biology Drug Resistance Neoplasm Cell culture 030220 oncology & carcinogenesis Cancer research medicine.drug |
| Zdroj: | Biomedicine & Pharmacotherapy. 97:844-850 |
| ISSN: | 0753-3322 |
| DOI: | 10.1016/j.biopha.2017.10.146 |
| Popis: | Objective Numerous studies suggested autophagy was involved in temozolomide (TMZ) resistance in glioma. Long non-coding RNA (lncRNA) CASC2 was shown to be downregulated in glioma tissues and cell lines, and was related to the TMZ resistance. However, whether CASC2 affects TMZ resistance through regulating autophagy is unknown. The aim of this study was to assess the role and mechanism of CASC2 in TMZ-induced drug resistance in glioma cells. Methods Glioma and the adjacent non-cancerous tissues from 32 patients were collected. The expressions of CASC2 and miR-193a-5p were determined by PCR, and their correlation was analyzed. The correlation between CASC2 expression and the clinical characteristics of patients was also studied. Glioma cells were treated with TMZ to acquire the TMZ-resistant cell lines in which the expressions of CASC2, miR-193a-5p, and mTOR were measured. The regulatory roles of CASC2, miR-193a-5p, and mTOR were defined through the loss of function and luciferase reporter assays. Autophagy was inhibited by autophagy inhibitor 3-MA, CASC2 and mTOR overexpression, or miR-193a-5p inhibitor, and the effect of which on cell viability, apoptosis, and migration of TMZ-resistant glioma cells was evaluated. Results CASC2 downregulation and miR-193a-5p upregulation was found to be associated with advanced clinical stage and TMZ response in patients with glioma. CASC2 negatively regulates miR-193a-5p expression by direct interaction in glioma cells. Overexpression of CASC2 or inhibition of miR-193a-5p reduced TMZ-induced autophagy via mTOR upregulation, which makes the glioma cells become sensitive to TMZ cytotoxicity. Conclusion CASC2 is downregulated in gliomas, resulting in increased miR-193a-5p level and a decrease in mTOR expression, which further induces protective autophagy, leading to TMZ resistance. Inhibition of autophagy helps to increase the efficacy of TMZ. |
| Databáze: | OpenAIRE |
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