在三阴性乳腺癌细胞系中，circUBR5通过miR-340-5p/CMTM6/c-MYC轴促进核糖体生物发生并诱导多西他赛耐药。

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia Pub Date : 2025-01-01 DOI:10.1016/j.neo.2024.101062

Xuedong Wang , Xinping Wang , Juan Gu , Yilei Wei , Yueping Wang

{"title":"在三阴性乳腺癌细胞系中，circUBR5通过miR-340-5p/CMTM6/c-MYC轴促进核糖体生物发生并诱导多西他赛耐药。","authors":"Xuedong Wang , Xinping Wang , Juan Gu , Yilei Wei , Yueping Wang","doi":"10.1016/j.neo.2024.101062","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><div>Docetaxel (DTX) represents an effective chemotherapeutic agent for treating triple-negative breast cancer (TNBC), but the efficacy is strongly limited by drug resistance. c-MYC-mediated ribosome biogenesis is considered a feasible strategy to confront chemoresistance in BC. We elucidated the impact of CMTM6 on TNBC DTX chemoresistance by governing c-MYC-mediated ribosome biogenesis, and its upstream ceRNA regulatory pathways.</div></div><div><h3>Methods</h3><div>DTX-resistant TNBC cells MDA-MB-231R and HCC1937R were generated by exposing sensitive cells MDA-MB-231 and HCC1937 to escalating doses of DTX. The expression patterns of CMTM6 and c-MYC were assessed by Western blot. The relationships between CMTM6 and miR-340-5p, circUBR5 and miR-340-5p were determined using bioinformatics analysis, luciferase assay, RIP, RNA in situ hybridization and biotin-labeled miR co-precipitation assay. Following ectopic expression and depletion experiments in DTX-resistant cells, cell chemoresistance, apoptosis, colony formation and nascent protein synthesis were evaluated.</div></div><div><h3>Results</h3><div>CMTM6 expression was elevated in DTX-resistant TNBC cells. CMTM6 knockdown enhanced apoptosis of DTX-resistant TNBC cells and increased their sensitivity to DTX by blocking c-MYC-mediated ribosome biogenesis. Mechanistically, miR-340-5p targeted CMTM6 and negatively regulated the expression of CMTM6 in DTX-resistant TNBC cells. Moreover, circUBR5 attenuated the repression on CMTM6 expression as a ceRNA for miR-340-5p. circUBR5 knockdown inactivated c-MYC-mediated ribosome biogenesis, and therefore enhanced DTX efficacy by promoting miR-340-5p binding to CMTM6.</div></div><div><h3>Conclusion</h3><div>circUBR5 knockdown facilitated miR-340-5p-targeted CMTM6 via a ceRNA mechanism, thereby reducing c-MYC-mediated ribosome biogenesis and accelerating chemosensitization of DTX-resistant TNBC cells, which offered a theoretical guideline for clinical research on the feasibility of inhibiting ribosome biogenesis to reduce TNBC chemoresistance.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101062"},"PeriodicalIF":4.8000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697786/pdf/","citationCount":"0","resultStr":"{\"title\":\"circUBR5 promotes ribosome biogenesis and induces docetaxel resistance in triple-negative breast cancer cell lines via the miR-340-5p/CMTM6/c-MYC axis\",\"authors\":\"Xuedong Wang , Xinping Wang , Juan Gu , Yilei Wei , Yueping Wang\",\"doi\":\"10.1016/j.neo.2024.101062\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><div>Docetaxel (DTX) represents an effective chemotherapeutic agent for treating triple-negative breast cancer (TNBC), but the efficacy is strongly limited by drug resistance. c-MYC-mediated ribosome biogenesis is considered a feasible strategy to confront chemoresistance in BC. We elucidated the impact of CMTM6 on TNBC DTX chemoresistance by governing c-MYC-mediated ribosome biogenesis, and its upstream ceRNA regulatory pathways.</div></div><div><h3>Methods</h3><div>DTX-resistant TNBC cells MDA-MB-231R and HCC1937R were generated by exposing sensitive cells MDA-MB-231 and HCC1937 to escalating doses of DTX. The expression patterns of CMTM6 and c-MYC were assessed by Western blot. The relationships between CMTM6 and miR-340-5p, circUBR5 and miR-340-5p were determined using bioinformatics analysis, luciferase assay, RIP, RNA in situ hybridization and biotin-labeled miR co-precipitation assay. Following ectopic expression and depletion experiments in DTX-resistant cells, cell chemoresistance, apoptosis, colony formation and nascent protein synthesis were evaluated.</div></div><div><h3>Results</h3><div>CMTM6 expression was elevated in DTX-resistant TNBC cells. CMTM6 knockdown enhanced apoptosis of DTX-resistant TNBC cells and increased their sensitivity to DTX by blocking c-MYC-mediated ribosome biogenesis. Mechanistically, miR-340-5p targeted CMTM6 and negatively regulated the expression of CMTM6 in DTX-resistant TNBC cells. Moreover, circUBR5 attenuated the repression on CMTM6 expression as a ceRNA for miR-340-5p. circUBR5 knockdown inactivated c-MYC-mediated ribosome biogenesis, and therefore enhanced DTX efficacy by promoting miR-340-5p binding to CMTM6.</div></div><div><h3>Conclusion</h3><div>circUBR5 knockdown facilitated miR-340-5p-targeted CMTM6 via a ceRNA mechanism, thereby reducing c-MYC-mediated ribosome biogenesis and accelerating chemosensitization of DTX-resistant TNBC cells, which offered a theoretical guideline for clinical research on the feasibility of inhibiting ribosome biogenesis to reduce TNBC chemoresistance.</div></div>\",\"PeriodicalId\":18917,\"journal\":{\"name\":\"Neoplasia\",\"volume\":\"59 \",\"pages\":\"Article 101062\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2025-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697786/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neoplasia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1476558624001039\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neoplasia","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1476558624001039","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}

引用次数: 0

摘要

目的：多西他赛（Docetaxel， DTX）是治疗三阴性乳腺癌（triple negative breast cancer， TNBC）的有效化疗药物，但其疗效受到耐药性的强烈限制。c- myc介导的核糖体生物发生被认为是对抗BC化疗耐药的可行策略。我们通过调控c- myc介导的核糖体生物发生及其上游ceRNA调控途径，阐明了CMTM6对TNBC DTX化学耐药的影响。方法：将敏感细胞MDA-MB-231和HCC1937暴露于剂量递增的DTX，产生耐药TNBC细胞MDA-MB-231R和HCC1937R。Western blot检测CMTM6和c-MYC的表达模式。采用生物信息学分析、荧光素酶测定、RIP、RNA原位杂交和生物素标记miR共沉淀法测定CMTM6与miR-340-5p、cirbr5和miR-340-5p之间的关系。通过dtx耐药细胞的异位表达和耗尽实验，评估了细胞的化学耐药、凋亡、集落形成和新生蛋白合成。结果：CMTM6在dtx耐药TNBC细胞中表达升高。CMTM6敲低可通过阻断c- myc介导的核糖体生物发生，增强DTX耐药TNBC细胞的凋亡并增加其对DTX的敏感性。在机制上，miR-340-5p靶向CMTM6并负向调节CMTM6在dtx耐药TNBC细胞中的表达。此外，作为miR-340-5p的ceRNA， circUBR5减弱了对CMTM6表达的抑制。circUBR5敲低使c- myc介导的核糖体生物发生失活，因此通过促进miR-340-5p与CMTM6的结合增强了DTX的功效。结论：cirbr5敲低通过ceRNA机制促进mir -340-5p靶向CMTM6，从而减少c- myc介导的核糖体生物生成，加速dtx耐药TNBC细胞的化疗增敏，为临床研究抑制核糖体生物生成降低TNBC化疗耐药的可行性提供了理论指导。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

circUBR5 promotes ribosome biogenesis and induces docetaxel resistance in triple-negative breast cancer cell lines via the miR-340-5p/CMTM6/c-MYC axis

Objective

Docetaxel (DTX) represents an effective chemotherapeutic agent for treating triple-negative breast cancer (TNBC), but the efficacy is strongly limited by drug resistance. c-MYC-mediated ribosome biogenesis is considered a feasible strategy to confront chemoresistance in BC. We elucidated the impact of CMTM6 on TNBC DTX chemoresistance by governing c-MYC-mediated ribosome biogenesis, and its upstream ceRNA regulatory pathways.

Methods

DTX-resistant TNBC cells MDA-MB-231R and HCC1937R were generated by exposing sensitive cells MDA-MB-231 and HCC1937 to escalating doses of DTX. The expression patterns of CMTM6 and c-MYC were assessed by Western blot. The relationships between CMTM6 and miR-340-5p, circUBR5 and miR-340-5p were determined using bioinformatics analysis, luciferase assay, RIP, RNA in situ hybridization and biotin-labeled miR co-precipitation assay. Following ectopic expression and depletion experiments in DTX-resistant cells, cell chemoresistance, apoptosis, colony formation and nascent protein synthesis were evaluated.

Results

CMTM6 expression was elevated in DTX-resistant TNBC cells. CMTM6 knockdown enhanced apoptosis of DTX-resistant TNBC cells and increased their sensitivity to DTX by blocking c-MYC-mediated ribosome biogenesis. Mechanistically, miR-340-5p targeted CMTM6 and negatively regulated the expression of CMTM6 in DTX-resistant TNBC cells. Moreover, circUBR5 attenuated the repression on CMTM6 expression as a ceRNA for miR-340-5p. circUBR5 knockdown inactivated c-MYC-mediated ribosome biogenesis, and therefore enhanced DTX efficacy by promoting miR-340-5p binding to CMTM6.

Conclusion

circUBR5 knockdown facilitated miR-340-5p-targeted CMTM6 via a ceRNA mechanism, thereby reducing c-MYC-mediated ribosome biogenesis and accelerating chemosensitization of DTX-resistant TNBC cells, which offered a theoretical guideline for clinical research on the feasibility of inhibiting ribosome biogenesis to reduce TNBC chemoresistance.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Neoplasia 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

26 days

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.