Journal
CANCER RESEARCH
Volume 82, Issue 21, Pages 4001-4015Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-22-0909
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Funding
- National Natural Science Foundation of China [81972472, 82173231, 31970696, 82172618]
- Natural Science Foundation of Anhui [2008085MH276]
- academic funding projects for top talents in disciplines and majors [gxbjZD2021045]
- research level promotion plan of Anhui Medical University [2021xkjT005]
- Scientific Research Platform and Base Upgrading Plan of Anhui Medical University [2021xkjT048]
- Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholar [LR22H160010]
- Shenzhen Key Laboratory of Inno-vative Oncotherapeutics (Shenzhen Science and Technology Innovation Commission) [ZDSYS20200820165400003]
- University Stable Funding Key Projects [WDZC20200821150704001]
- Shenzhen Development and Reform Commission Subject Construction Project [[2017] 1434]
- TBSI Faculty Start-up Funds
- Shenzhen Bay Laboratory, P.R. China
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A novel p62 mRNA isoform that escapes miRNA-mediated repression and leads to increased p62 protein expression was found to be associated with chemoresistance in breast cancer cells and tissue specimens.
Resistance to chemotherapy remains a major obstacle to the successful treatment of breast cancer. More than 80% of patients who receive neoadjuvant chemotherapy (NAC) do not achieve a pathologic complete response. In this study, we report a novel p62 mRNA isoform with a short 3'-UTR (untranslated region; p62-SU, 662-nt) that is associated with chemoresistance in breast cancer cells and tissue specimens. The p62 mRNA iso-form was identified by RNA sequencing with qRT-PCR, 3'-RACE, and Northern blot analysis. In vitro and in vivo, ectopic expression of p62-SU promoted breast cancer cell pro-liferation, migration, invasion, and chemoresistance compared with the p62 mRNA isoform with a full-length 3'-UTR (p62-LU, 1,4 85-nt). Mechanistically, cleavage and polyadenylation spe-cific factor 1 (CPSF1) modulated the 3'-UTR of p62 through alternative polyadenylation. In addition, p62-SU escaped miR-124-3p-mediated repression and upregulated p62-SU protein expression, thereby inducing p62-dependent chemoresistance. These data suggest that a CPSF1-p62-miR-124-3p signaling axis is responsible for reduced sensitivity of breast cancer to chemotherapy. Significance: Resistance to NAC in breast cancer is driven by a novel p62 mRNA isoform that escapes miRNA-mediated repres-sion and leads to increased p62 protein expression. [GRAPHICS] .
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