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.
Highlights
According to the Chinese Cancer Report 2019 and the World Health Organization (WHO) Global Cancer Report 2020, breast cancer is the highest incidence of malignant tumors in female and is one of the main causes of female malignant tumor death [1]
Strawberry 5.3; miRNAs were collected from transcriptional profile; 144 DNA damage response (DDR)-associated genes were collected from literature review, and the expression profile was extracted from transcriptional profile (RNA sequence data, from The Cancer Genome Atlas (TCGA)) with the help of Perl Strawberry 5.3; miRNA targeted genes were identified by combination analysis from miRDB, miRTarBase and TargetScan database, with the help of
Recognition of prognosis-related miRNAs which was involved in autophagy and genomic instability (GIN)
Summary
According to the Chinese Cancer Report 2019 and the World Health Organization (WHO) Global Cancer Report 2020, breast cancer is the highest incidence of malignant tumors in female and is one of the main causes of female malignant tumor death [1]. Up to 30%~50% chemotherapy resistance makes limited effects of combining drug treatment strategy, which lead bad prognosis [2]. Genomic instability (GIN) is pivotal for tumor initiation and progression [3]. Tumor cells usually hold DDR defects and are prone to genetic alteration under the drug-induced microenvironment pressure, that is, gene copy number changes, chromosomal rearrangements, and gene mutations, which lead to tumor progression [3]. In familial breast cancer, the direct loss, imbalance of expression and abnormal function of DDR protein (TP53, BRCA1, ATM, etc.) have led to an increased risk of breast cancer, the development of malignant subtypes, and tumor chemotherapy resistance [4]
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