CircFBXL5 promotes the 5-FU resistance of breast cancer via modulating miR-216b/HMGA2 axis

Abstract

Background Circular RNAs (circRNAs) have been confirmed to be relevant to the 5-fluorouracil (5-FU) resistance of breast cancer. Nevertheless, how and whether circRNA F-box and leucine-rich repeat protein 5 (circFBXL5) regulates the 5-FU resistance of breast cancer is uncertain. This study aims to explore the function and mechanism of circFBXL5 in the 5-FU resistance of breast cancer. Methods Thirty nine paired breast cancer and normal tissues were harvested. circFBXL5, microRNA-216b (miR-216b) and high-mobility group AT-hook 2 (HMGA2) abundances were examined via quantitative reverse transcription polymerase chain reaction or western blot. Cell viability, 5-FU resistance, migration, invasion, and apoptosis were tested via cell counting kit-8 assay, wound healing analysis, transwell analysis, and flow cytometry. The relationship of miR-216b and circFBXL5 or HMGA2 was tested via dual-luciferase reporter analysis and RNA pull-down assay. The impact of circFBXL5 on breast cancer tumor growth in vivo was analyzed via xenograft model. Results circFBXL5 was highly expressed in breast cancer tissues and cells, and was more upregulated in 5-FU-resistant breast cancer cells. Function experiments showed that circFBXL5 knockdown inhibited the 5-FU resistance of breast cancer by inhibiting cell migration, invasion and promoting apoptosis. In the terms of mechanism, miR-216b could be sponged by circFBXL5, and its inhibitor could also reverse the influence of circFBXL5 silencing on the 5-FU resistance of breast cancer cells. In addition, HMGA2 was a target of miR-216b, and its overexpression also reversed the regulation of miR-216b overexpression on the 5-FU resistance of breast cancer. Furthermore, circFBXL5 interference declined breast cancer tumor growth in xenograft model. Conclusion Our data showed that circFBXL5 could promote the 5-FU resistance of breast cancer by regulating miR-216b/HMGA2 axis.

Current evidence on circRNAs as potential theranostic markers for detecting chemoresistance in breast cancer: a systematic review and meta‑analysis

“…Studies have shown that abnormal circRNA expression is important in tumor cell proliferation, metastasis and cancer recurrence in BC patients [10][11][12][20][21][22][23][24][25][26][27][28][29][30][31][32][35][36][37][38][39] . Many studies have also confirmed that several specific circRNAs are consistently expressed in human tissues and blood.…”

Long noncoding RNA CRART16 confers 5-FU resistance in colorectal cancer cells by sponging miR-193b-5p

“…Numerous studies have revealed that HMGA2 is overexpressed in many cancer cells [ 35 ], and overexpression of HMGA2 is correlated with progression and a poor prognosis in various malignancies, including CRC [ 36 – 40 ]. Furthermore, several studies have demonstrated that HMGA2 participates in 5-FU resistance in some malignancies, such as CRC [ 39 , 41 , 42 ], breast cancer [ 43 , 44 ], and liver cancer [ 45 ]. For example, Zheng et al [ 41 ] revealed that HMGA2 could promote 5-FU resistance, which could be reversed by miR-9-5p, in CRC cells.…”

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

“…CircFBXL5 knockdown enhanced the 5-FU sensitivity in the BC cells by suppressing cell migration and invasion and facilitating apoptosis. Mechanistically, circFBXL5 promoted 5-FU resistance by upregulating HMGA2 via sequestrating miR-216b ( 294 ). Oncogenic ncRNAs, such as miRNA-3662 and circFBXL5, might be used as ideal candidates for therapeutic targets.…”