MicroRNA-149 Increases the Sensitivity of Colorectal Cancer Cells to 5-Fluorouracil by Targeting Forkhead Box Transcription Factor FOXM1

• Published in: Cellular physiology and biochemistry Vol. 39; no. 2; pp. 617 - 629
• Main Authors: Liu, Xiaobei, Xie, Tao, Mao, Xiaobei, Xue, Lijun, Chu, Xiaoyuan, Chen, Longbang
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland Cell Physiol Biochem Press GmbH & Co KG 01.01.2016
• Subjects: 3' Untranslated Regions - genetics; 5-Fluorouracil; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Blotting, Western; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Chemoresistance; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Fluorouracil - administration & dosage; Fluorouracil - pharmacology; Forkhead Box Protein M1 - genetics; Forkhead Box Protein M1 - metabolism; FOXM1; Gene Expression Regulation, Neoplastic - drug effects; Humans; MicroRNA-149; MicroRNAs - genetics; MicroRNAs - metabolism; Original Paper; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction - drug effects; Signal Transduction - genetics; MicroRNA-149; 5-Fluorouracil; FOXM1; Chemoresistance; Colorectal cancer
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000445653

Background/Aims: Previously, we have shown that microRNA (miR)-149 suppresses the migration and invasion of colorectal cancer (CRC) cells by targeting forkhead box transcription factor (FOXM1). However, the roles of miR-149 in the chemoresistance of CRC cells to 5-Fluorouracil (5-FU) is unclear. The aim of this study is to investigate whether miR-149 targets FOXM1 to regulate the 5-FU resistance of CRC. Methods: The qRT-PCR assay was performed to detect the expression of miR-149 in 5-FU-resistant CRC cells (HCT-8/5-FU and LoVo/5-FU) and their parental CRC cells (HCT-8 and LoVo). Also, the effects of miR-149 expression on the sensitivity of CRC cells to 5-FU were determined by gain- and loss-of-function assays. Finally, whether miR-149 regulates the 5-FU resistance of CRC cells by targeting the mammalian Forkhead Box M1 (FOXM1) was investigated. Results: The expression of miR-149 was significantly downregulated in 5-FU-resistant CRC cells in comparison with their parental CRC cells. Re-expression of miR-149 could enhance the 5-FU sensitivity of 5-FU-resistant CRC cells by increasing 5-FU-inducing apoptosis, while downregulation of miR-149 could decrease the 5-FU sensitivity of parental CRC cells by decreasing 5-FU-inducing apoptosis. In addition, the luciferase assay indicated that miR-149 could bind to the 3'-UTR sequence of FOXM1 mRNA. The silencing of FOXM1 could mimic the effect of miR-149 upregulation on the 5-FU resistance of 5-FU-resistant CRC cells. Furthermore, the expression of miR-149 in the 5-FU-responding CRC tissues was significantly higher than that in the non-responding tissues and inversely correlated with FOXM1 mRNA level. Conclusions: MiR-149 reverses the resistance of CRC cells to 5-FU by directly targeting FOXM1. Thus, targeting miR-149/FOXM1 signaling will be a potential strategy in the treatment of 5-FU-chemoresistant CRC.