Knockdown of circ_0004585 enhances the chemosensitivity of colorectal cancer cells to 5-fluorouracil via the miR-874-3p/CCND1 axis

Abstract

Background: Colorectal cancer (CRC) is a serious threat to human health and is drug-resistant. Circular RNA _0004585 (circ_0004585) has been shown to be expressed in CRC, but whether it plays a role in CRC with chemoresistance remains unknown. Therefore, this study aimed to investigate the potential role of circ_0004585 in CRC with 5-fluorouracil (5-FU) resistance.

Methods: The expression of related genes was detected by quantitative real-time polymerase chain reaction (qRT-PCR), and the protein expressions of cleaved caspase-3, cleaved caspase-9, and cyclin D1 (CCND1) were detected by western blot. Cell functions were identified using CCK-8, colony formation, flow cytometry, tube formation and transwell assays. The putative relationships between miR-874-3p and circ_0004585 or CCND1 were validated by dual-luciferase reporter assays. Animal experiments were conducted to verify the effect of circ_0004585 on 5-FU resistance in vivo.

Results: Circ_0004585 was highly expressed in CRC tissues and cells, particularly in 5-FU-resistant CRC tissues and cells. Circ_0004585 knockdown enhanced 5-FU sensitivity to further inhibit CRC cell viability, colony formation, cell migration and invasion, and accelerate cell apoptosis. MiR-874-3p was the target of circ_0004585, and miR-874-3p depletion partially recovered the malignant behaviors of 5-FU-resistant CRC cells that were blocked by silencing of circ_0004585. In addition, CCND1 was the target of miR-874-3p, and overexpression of CCND1 was able to restore the malignant effects of 5-FU-resistant CRC cells that were repressed by miR-874-3p enrichment. Animal experiments confirmed that circ_0004585 knockdown inhibited the growth of CRC tumors and enhanced 5-FU sensitivity in vivo.

Conclusion: Circ_0004585 promotes the development of CRC and increases 5-FU resistance in CRC through the miR-874-3p/CCND1 axis. These results suggest that circ_0004585 may be a therapeutic target for 5-FU-ressitant CRC.