LncRNA OTUD6B-AS1 promotes paclitaxel resistance in triple negative breast cancer by regulation of miR-26a-5p/MTDH pathway-mediated autophagy and genomic instability

被引:0
作者
Li, Peng-Ping [1 ]
Li, Rong-Guo [1 ]
Huang, Yu-Qing [1 ]
Lu, Jin-Pian [2 ]
Zhang, Wei-Jun [1 ]
Wang, Zhen-Yu [1 ]
机构
[1] First Hosp Xiaoshan Dist, Dept Gen Surg, Dept Breastthyroid Surg, Hangzhou 311000, Zhejiang, Peoples R China
[2] Zhejiang Chinese Med Univ, Affiliated Hosp 2, Hangzhou 310000, Zhejiang, Peoples R China
来源
AGING-US | 2021年 / 13卷 / 21期
关键词
y chemotherapy resistance; autophagy; genomic instability (GIN); triple negative breast cancer (TNBC); DNA damage response (DDR); DNA; PROLIFERATION; SENSITIVITY; INHIBITION; CARCINOMA; INVASION; GROWTH; REPAIR; DAMAGE; CELLS;
D O I
暂无
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Genomic instability (GIN) is pivotal in regulating tumor drug resistance, which blocked the treatment of triple negative breast cancer (TNBC). Although recent studies implied that non-coding RNA (ncRNA)-mediated autophagy abolishment promoted tumorigenesis by up-regulation of GIN, autophagy was known as a risk factor in tumor drug resistance. However, previous study also pointed that up-regulation of autophagy promoted GIN. Therefore, the relationship between autophagy and GIN is not clear, and more work is needed. And, if an ncRNA is identified to be a co-regulator of autophagy and GIN, it will be a potential therapy target of chemotherapy resistance in TNBC. In our study, we recognized both autophagy-GIN-associated microRNA (mi-26a-5p) by big data analysis, which was prognosis-correlated in breast cancer. Next, we identified the up-stream regulators (long non-coding RNA, lncRNA) and down-stream targets of miR-26a-5p by bioinformatics analysis (online public databases). Finally, we established lncRNA OTUD6B-AS1/miR-26a-5p/MTDH signaling pathway, and verified their functions by cytological, molecular biological and zoological experiments. In general, our study found (1) miR-26a-5p was a protective factor of breast cancer, while OTUD6B-AS1 and MTDH were risk factors; (2) OTUD6B-AS1 was the up-stream regulator of miR-26a-5p verified by luciferase; (3) up regulation of miR-26a-5p and down-regulation of MTDH promoted cellular cytotoxicity of paclitaxel (PTX) in vitro and in vivo. (4) down-regulation of miR-26a-5p, overexpression of MTDH and OTUD6B-AS1 promoted autophagy and DNA damage; (5) up-regulation of OTUD6B-AS1 and MTDH inhibited DNA damage response (DDR) by inhibiting the phosphorylated activation of RAD51, ATR and ATM.
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收藏
页码:24171 / 24191
页数:21
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