Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR-193a-5p and regulating mTOR expression

被引：88

作者：

Jiang, Chunming ^{[1
]}

Shen, Fang ^{[2
]}

Du, Jianmin ^{[1
]}

Fang, Xiang ^{[3
]}

Li, Xiaoli ^{[1
]}

Su, Jin ^{[4
]}

Wang, Xiaohua ^{[5
]}

Huang, Xianmei ^{[1
]}

Liu, Zhangli ^{[1
]}

机构：

[1] Zhejiang Chinese Med Univ, Nanjing Med Univ, Hangzhou Peoples Hosp 1, Clin Med Coll 4,Dept Pediat, 261 Huansha Rd, Hangzhou 310003, Zhejiang, Peoples R China

[2] Tongde Hosp Zhejiang Prov, Dept Psychiat, Hangzhou 310012, Zhejiang, Peoples R China

[3] Zhejiang Chinese Med Univ, Nanjing Med Univ, Hangzhou Peoples Hosp 1, Clin Med Coll 4,Dept Clin Lab, Hangzhou 310003, Zhejiang, Peoples R China

[4] Nanjing Med Univ, Affiliated Hosp 1, Dept Pediat, Nanjing 210029, Jiangsu, Peoples R China

[5] Nanjing Med Univ, Nanjing Hosp 1, Dept Pediat, Nanjing 210029, Jiangsu, Peoples R China

来源：

BIOMEDICINE & PHARMACOTHERAPY | 2018年 / 97卷

关键词：

lncRNA-CASC2; Glioma; Chemoresistance; Autophagy; miR-193a-5p; mTOR; NONCODING RNA CASC2; CANCER; GLIOBLASTOMA; RESISTANCE; MICRORNAS; LNCRNA; PROLIFERATION; ANTAGONIZES; SUPPRESSES; PATHWAY;

D O I：

10.1016/j.biopha.2017.10.146

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：844 / 850

页数：7

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