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

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

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.

Keywords: MSI1; chemosensitivity; circ_0032833; colorectal cancer; miR-125-5p.

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