title: The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression.
abstract: Chemoresistance hinders the curative cancer chemotherapy. To define the role of the DNA methylation-regulated microRNA (miR) genes in the chemoresistance of bladder cancer, we performed both DNA methylomic and miRomic analyses of a multi-chemosensitive (5637) versus a multi-chemoresistant (H-bc) cell line and found that miR-193a-3p is hypermethylated/silenced in 5637 and hypomethylated/expressed in H-bc cells. A forced reversal of its level turned around the chemoresistance in the cultured cells and the tumor xenografts in nude mice. Three of its targets: SRSF2, PLAU and HIC2, work in concert to relay the miR-193a-3p's impact on the bladder cancer chemoresistance by modulating the activities of the following five signaling pathways: DNA damage, Notch, NF-κB, Myc/Max, and Oxidative Stress. In addition to the mechanistic insights in how the newly identified miR-193a-3p/SRSF2,PLAU,HIC2/five signaling pathway axis regulates the chemoresistance of bladder cancer cells, our study provides a new set of diagnostic targets for the guided personalized chemotherapy of bladder cancer.
authors.affiliation: Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China.
authors.forename: L
authors.initials: L
authors.lastname: Lv
authors.affiliation: Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China.
authors.forename: H
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Biology, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics, MHBI (Shanghai) Biotech Inc., GuiPing Road 333, Building 4/104, Shanghai Juke Biotech Park, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Pu
authors.affiliation: Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China.
authors.forename: T
authors.initials: T
authors.lastname: Yu
authors.affiliation: 1] Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China [2] Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhu
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use / Q000633:toxicity; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D020413:3' Untranslated Regions; D000972:Antineoplastic Agents, Phytogenic; C436951:HIC2 protein, human; D051741:Kruppel-Like Transcription Factors; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D012261:Ribonucleoproteins; D025521:Tumor Suppressor Proteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D010960:Plasminogen Activators