title: MicroRNA-149 Increases the Sensitivity of Colorectal Cancer Cells to 5-Fluorouracil by Targeting Forkhead Box Transcription Factor FOXM1.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing Clinical Medical College of Second Military Medical University, Nanjing, PR China.
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Mao
authors.forename: Lijun
authors.initials: L
authors.lastname: Xue
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chu
authors.forename: Longbang
authors.initials: L
authors.lastname: Chen
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D000072278:Forkhead Box Protein M1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C551557:MIRN149 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D005472:Fluorouracil