CircLIFR synergizes with MSH2 to attenuate chemoresistance via MutSα/ATM-p73 axis in bladder cancer.
CircLIFR synergizes with MSH2 to attenuate chemoresistance via MutSα/ATM-p73 axis in bladder cancer.
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CircLIFR 与 MSH2 协同作用，通过 MutSα/ATM-p73 轴减弱膀胱癌的化疗耐药性
DOI：
10.1186/s12943-021-01360-4
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发表时间：
2021-04-19
期刊：
影响因子：
37.3
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Zhang H;Xiao X;Wei W;Huang C;Wang M;Wang L;He Y;Sun J;Jiang Y;Jiang G;Zhang X
背景顺铂（CDDP）已成为肌层浸润性膀胱癌（MIBC）的标准治疗方法，但耐药性仍是一个主要挑战。越来越多的证据表明，环状RNA（circRNA）是离散的功能实体。方法通过分析膀胱癌组织中circRNA的表达谱、RNA FISH、circRNA pull-down分析、质谱分析和RIP等方法，鉴定circLIFR，并证实其与MSH 2的相互作用。通过流式细胞术和挽救实验探讨circLIFR和MSH 2对基于CDDP的化疗的影响。采用Co-IP和Western blot方法研究circLIFR和MSH 2的分子机制。CircLIFR和MSH 2在膀胱癌中的生物学意义在肿瘤异种移植模型和PDX models.ResultsCircLIFR在膀胱癌中表达下调，表达与良好的预后呈正相关。此外，circLIFR协同MSH 2，这是一个介导的CDDP敏感性膀胱癌细胞，积极调制敏感性CDDP在体外和体内。从机制上讲，circLIFR增强了MutSα和ATM之间的相互作用，最终有助于稳定p73，从而引发凋亡。结论CircLIFR与MSH 2通过MutSα/ATM-p73轴相互作用，对膀胱癌CDDP敏感性产生正性调节作用。CircLIFR和MSH 2有可能成为CDDP耐药膀胱癌治疗的靶点。
BackgroundCisplatin (CDDP) has become a standard-of-care treatment for muscle-invasive bladder cancer (MIBC), while chemoresistance remains a major challenge. Accumulating evidence indicates that circular RNAs (circRNAs) are discrete functional entities. However, the regulatory functions as well as complexities of circRNAs in modulating CDDP-based chemotherapy in bladder cancer are yet to be well revealed.MethodsThrough analyzing the expression profile of circRNAs in bladder cancer tissues, RNA FISH, circRNA pull-down assay, mass spectrometry analysis and RIP, circLIFR was identified and its interaction with MSH2 was confirmed. The effects of circLIFR and MSH2 on CDDP-based chemotherapy were explored by flow cytometry and rescue experiments. Co-IP and Western blot were used to investigate the molecular mechanisms underlying the functions of circLIFR and MSH2. Biological implications of circLIFR and MSH2 in bladder cancer were implemented in tumor xenograft models and PDX models.ResultsCircLIFR was downregulated in bladder cancer and expression was positively correlated with favorable prognosis. Moreover, circLIFR synergizing with MSH2, which was a mediator of CDDP sensitivity in bladder cancer cells, positively modulated sensitivity to CDDP in vitro and in vivo. Mechanistically, circLIFR augmented the interaction between MutSα and ATM, ultimately contributing to stabilize p73, which triggered to apoptosis. Importantly, MIBC with high expression of circLIFR and MSH2 was more sensitive to CDDP-based chemotherapy in tumor xenograft models and PDX models.ConclusionsCircLIFR could interact with MSH2 to positively modulate CDDP-sensitivity through MutSα/ATM-p73 axis in bladder cancer. CircLIFR and MSH2 might be act as promising therapeutic targets for CDDP-resistant bladder cancer.
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