1. LncRNA OTUD6B-AS1 promotes paclitaxel resistance in triple negative breast cancer by regulation of miR-26a-5p/MTDH pathway-mediated autophagy and genomic instability
- Author
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Wei-Jun Zhang, Jin-Pian Lu, Peng-Ping Li, Rong-Guo Li, Zhen-Yu Wang, and Yu-Qing Huang
- Subjects
Genome instability ,Aging ,chemotherapy resistance ,autophagy ,Paclitaxel ,DNA damage ,Mice, Nude ,Antineoplastic Agents ,Triple Negative Breast Neoplasms ,Biology ,medicine.disease_cause ,DNA damage response (DDR) ,Genomic Instability ,triple negative breast cancer (TNBC) ,Cell Line, Tumor ,microRNA ,medicine ,Animals ,Humans ,genomic instability (GIN) ,Triple-negative breast cancer ,Autophagy ,Membrane Proteins ,RNA-Binding Proteins ,MTDH ,Cell Biology ,Non-coding RNA ,MicroRNAs ,Drug Resistance, Neoplasm ,Cancer research ,Female ,RNA, Long Noncoding ,Carcinogenesis ,Research Paper - Abstract
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.
- Published
- 2021