An Alternatively Spliced p62 Isoform Confers Resistance to Chemotherapy in Breast Cancer
An Alternatively Spliced p62 Isoform Confers Resistance to Chemotherapy in Breast Cancer
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DOI：
10.1158/0008-5472.can-22-0909
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发表时间：
2022-11-01
期刊：
影响因子：
11.2
通讯作者：
Wu, Zhengsheng
中科院分区：
文献类型：
--
作者：
Guo, Qianying;Wang, Hao;Wu, Zhengsheng
对化疗的耐药性仍然是成功治疗乳腺癌的主要障碍。超过80%的接受新辅助化疗（NAC）的患者没有达到病理完全缓解。在这项研究中，我们报告了一种新的p62 mRNA亚型，具有短的3 '-UTR（非翻译区; p62-SU，662-nt），与乳腺癌细胞和组织标本中的化疗耐药性相关。通过qRT-PCR、3 '-RACE和北方印迹分析的RNA测序鉴定p62 mRNA同种型。在体外和体内实验中，与具有全长3 '-UTR的p62 mRNA异构体（p62-LU，1，4 85-nt）相比，p62-SU的异位表达促进乳腺癌细胞的增殖、迁移、侵袭和化疗抗性。切割和多聚腺苷酸化特异性因子1（CPSF 1）通过选择性多聚腺苷酸化调节p62的3 '-UTR。此外，p62-SU逃脱了miR-124- 3 p介导的抑制，上调了p62-SU蛋白表达，从而诱导了p62依赖性化疗耐药性。这些数据表明，CPSF 1-p62-miR-124- 3 p信号轴是乳腺癌化疗敏感性降低的原因。意义：乳腺癌对NAC的耐药是由一种新的p62 mRNA亚型驱动的，这种亚型逃避了miRNA介导的抑制，导致p62蛋白表达增加。[图形]。
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].