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Circ_0032833的下调使结直肠癌对5-氟尿嘧啶和奥沙利铂敏感，部分取决于miR-125-5p和MSI1的调控。

Down-Regulation of Circ_0032833 Sensitizes Colorectal Cancer to 5-Fluorouracil and Oxaliplatin Partly Depending on the Regulation of miR-125-5p and MSI1.

作者信息

Li Shouchao, Zheng Sheng

机构信息

Department of Anorectal Surgery, Weifang People's Hospital, Weifang 261000, People's Republic of China.

出版信息

Cancer Manag Res. 2020 Nov 4;12:11257-11269. doi: 10.2147/CMAR.S270123. eCollection 2020.

DOI:10.2147/CMAR.S270123
PMID:33177876
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7649231/
Abstract

BACKGROUND

5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is an effective chemotherapy for colorectal cancer (CRC) in clinic. It remains unclear regarding the effect of circular RNA (circRNA) circ_0032833 on regulating chemosensitivity in CRC.

METHODS

Drug resistance analysis was performed by Cell Counting Kit-8 (CCK-8) assay. All RNA and protein levels were, respectively, measured via quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Cellular colony capacity, apoptosis and metastasis were evaluated using colony formation assay, Annexin-FITC/PI flow cytometry and transwell migration/invasion assays. The molecular combination was notarized using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The in vivo experiment was conducted via xenograft tumors in mice.

RESULTS

Circ_0032833 was significantly up-regulated in FOLFOX-resistant CRC and associated with drug resistance. Knockdown of circ_0032833 could sensitize FOLFOX-resistant CRC cells to 5-fluorouracil and oxaliplatin. Circ_0032833 was a miR-125-5p sponge, and miR-125-5p overexpression was responsible for the effect of circ_0032833 knockdown on 5-fluorouracil and oxaliplatin sensitivities. Besides, miR-125-5p targeted Musashi1 (MSI1) to increase the susceptibility of 5-fluorouracil and oxaliplatin in FOLFOX-resistant CRC cells. We found that circ_0032833 generated the regulation on MSI1 by sponging miR-125-5p. Circ_0032833 down-regulation also promoted the 5-fluorouracil and oxaliplatin sensitivities partly through the miR-125-5p/MSI1 axis in vivo.

CONCLUSION

This study illuminated an unambiguous mechanism circ_0032833/miR-125-5p/MSI1 on regulating 5-fluorouracil and oxaliplatin sensitivities in FOLFOX therapy, maybe providing a deep insight of resistance formation and developing a novel strategy to enhance chemosensitivity in CRC.

摘要

背景

5-氟尿嘧啶、亚叶酸钙和奥沙利铂（FOLFOX）是临床上治疗结直肠癌（CRC）的一种有效化疗方案。关于环状RNA（circRNA）circ_0032833对CRC化疗敏感性调节的影响尚不清楚。

方法

采用细胞计数试剂盒-8（CCK-8）法进行耐药性分析。所有RNA和蛋白质水平分别通过定量实时聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法检测。使用集落形成试验、膜联蛋白-FITC/PI流式细胞术和transwell迁移/侵袭试验评估细胞集落形成能力、细胞凋亡和转移情况。使用双荧光素酶报告基因和RNA免疫沉淀（RIP）试验验证分子相互作用。通过小鼠异种移植瘤进行体内实验。

结果

circ_0032833在对FOLFOX耐药的CRC中显著上调，并与耐药相关。敲低circ_0032833可使对FOLFOX耐药的CRC细胞对5-氟尿嘧啶和奥沙利铂敏感。circ_0032833是miR-125-5p的海绵，miR-125-5p过表达介导了circ_0032833敲低对5-氟尿嘧啶和奥沙利铂敏感性的影响。此外，miR-125-5p靶向Musashi1（MSI1）以增加对FOLFOX耐药的CRC细胞对5-氟尿嘧啶和奥沙利铂的敏感性。我们发现circ_0032833通过海绵吸附miR-125-5p对MSI1产生调控作用。在体内，circ_0032833下调也部分通过miR-125-5p/MSI1轴促进了5-氟尿嘧啶和奥沙利铂的敏感性。

结论

本研究阐明了circ_0032833/miR-125-5p/MSI1在FOLFOX治疗中调节5-氟尿嘧啶和奥沙利铂敏感性的明确机制，可能为深入了解耐药形成机制及制定增强CRC化疗敏感性的新策略提供思路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/7182752463d8/CMAR-12-11257-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/dfef03ceceb3/CMAR-12-11257-g0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/b1b8534385cc/CMAR-12-11257-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/2e68f9607dd1/CMAR-12-11257-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/cc2a2358dac0/CMAR-12-11257-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/d539051ffd0a/CMAR-12-11257-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/7182752463d8/CMAR-12-11257-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/dfef03ceceb3/CMAR-12-11257-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/8302a21b16d0/CMAR-12-11257-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/681a7c541eea/CMAR-12-11257-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/0ebf742f2b8d/CMAR-12-11257-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/b1b8534385cc/CMAR-12-11257-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/2e68f9607dd1/CMAR-12-11257-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/cc2a2358dac0/CMAR-12-11257-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/d539051ffd0a/CMAR-12-11257-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db74/7649231/7182752463d8/CMAR-12-11257-g0009.jpg

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