title: Increased fucosylation has a pivotal role in multidrug resistance of breast cancer cells through miR-224-3p targeting FUT4.
abstract: Fucosylation is the final step in the glycosylation machinery, which produces glycans involved in tumor multidrug resistance development. MicroRNAs (miRNAs) are endogenous negative regulators of gene expression and have been implicated in most cellular processes of tumors, including drug resistance. This study was undertaken to determine the roles of fucosylation and miR-224-3p in multidrug resistance of human breast cancer cell lines. Comparative analysis revealed differential modification patterns of fucosylation of the fucosylated N-glycans in drug-resistant T47D/ADR cells and sensitive line T47D cells. The expressional profiles of fucosyltransferase genes in two pairs of parental and chemoresistant human breast cancer cell lines showed that FUT4 was up-regulated highly in MDR cell lines. Altered level of FUT4 affected the drug-resistant phenotype of T47D and T47D/ADR cells both in vitro and in vivo. By bioinformatics analysis, we identified FUT4 as one of the miR-224-3p-targeted genes. Further studies showed an inverse relationship between of FUT4 and miR-224-3p in parental and ADR-resistant breast cancer cells, wherein miR-224-3p was downregulated in resistant cells. 3'-UTR dual-luciferase reporter assay confirmed that miR-224-3p directly targeted 3'-untranslation region (3'-UTR) of FUT4 mRNA. In addition, miR-224-3p overexpression sensitized T47D/ADR cells to chemotherapeutics and reduced the growth rate of breast cancer xenografts in vivo. Our results indicate that FUT4 and miR-224-3p are crucial regulators of cancer response to chemotherapy, and may serve as therapeutic targets to reverse chemotherapy resistance in breast cancer.
authors.affiliation: College of Laboratory Medicine, Dalian Medical University, Dalian 116044, Liaoning Province, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Feng
authors.affiliation: College of Laboratory Medicine, Dalian Medical University, Dalian 116044, Liaoning Province, China.
authors.forename: Lifen
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China.
authors.forename: Shuhang
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Biochemistry, Dalian Medical University, Dalian 116044, Liaoning Province, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Dong
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, Liaoning Province, China.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Microbiology, Dalian Medical University, Dalian 116044, Liaoning Province, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Laparoscopic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, Liaoning Province, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Miao
authors.affiliation: College of Laboratory Medicine, Dalian Medical University, Dalian 116044, Liaoning Province, China. Electronic address: jiali0386@sina.com.
authors.forename: Li
authors.initials: L
authors.lastname: Jia
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005647:Fucosyltransferases / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D016256:Lewis X Antigen / Q000096:biosynthesis / Q000235:genetics*; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D011134:Polysaccharides / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D016256:Lewis X Antigen; C546140:MIRN224 microRNA, human; D035683:MicroRNAs; D011134:Polysaccharides; D012333:RNA, Messenger; D004317:Doxorubicin; C066693:FUT4 protein, human; D005647:Fucosyltransferases
keywords: Fucosylated N-glycan; Fucosyltransferase; Human breast cancer cell lines; Multidrug resistance; miR-224-3p