MiR-142-3p Overexpression Increases Chemo-Sensitivity of NSCLC by Inhibiting HMG B1-Mediated Autophagy

被引:63
作者
Chen, Yuqing [1 ]
Zhou, Xin [1 ]
Qiao, Jianou [2 ]
Bao, Aihua [1 ]
机构
[1] Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Resp, 100 Haining Rd, Shanghai 200080, Peoples R China
[2] Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 9, Shanghai, Peoples R China
关键词
miR-142-3p; HMGB1; Autophagy; NSCLC; PI3K/Akt/mTOR pathway; CELL LUNG-CANCER; POTENTIAL TUMOR-SUPPRESSOR; TARGETING AUTOPHAGY; DRUG-RESISTANCE; EXPRESSION; MICRORNAS; EGFR; PROLIFERATION; PI3K/AKT/MTOR; STRATEGIES;
D O I
10.1159/000467896
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Background: Non-small-cell lung cancer (NSCLC) is a deadly cancer with high mortality rate. Drug resistance represents a main obstacle in NSCLC treatment. High mobility group box-1 (HMGB1) protein promotes drug resistance in NSCLC cells by activating protective autophagy. Methods: In the current study, we investigated the regulatory role of microRNA-142-3p (miR-142-3p) in HMGB1-mediated autophagy of NSCLC cells and its impact on drug resistance of NSCLC in vitro and in vivo. HMGB1 was identified as a putative target gene of miR-142-3p by in sitico analysis. Our luciferase reporter assay results confirmed that miR-142-3p directly targets the 3'-UTR of HMGB1 in NSCLC cells. Results: MiR-142-3p overexpression suppressed while miR-142-3p knockdown increased HMGB1 mRNA and protein expression. Starvation induced HMGB1 expression and activated autophagy in NSCLC cells. The starvation-induced autophagy was inhibited by miR-142-3p overexpression or HMGB1 knockdown. Moreover, miR-142-3p overexpression or HMGB1 knockdown increased PI3K, Akt, and mTOR phosphorylation. Inhibition of PI3K or mTOR restored starvation-induced autophagy inhibited by miR-142-3p overexpression or HMGB1 knockdown. Conclusions: These results demonstrated that miR-142-3p regulates starvation-induced autophagy of NSCLC cells by directly downregulating HMGB1 and subsequently activating the PI3K/Akt/mTOR pathway. Further, miR-142-3p overexpression inhibited anticancer drug -induced autophagy and increased chemo-sensitivity of NSCLC in vitro and in vivo. These findings shed light on the therapeutic potential of miR-142-3p in combating acquired NSCLC chemo-resistance. (C) 2017 The Author(s) Published by S. Karger AG, Basel
引用
收藏
页码:1370 / 1382
页数:13
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