The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression

L Lv; H Deng; Y Li; C Zhang; X Liu; Q Liu; D Zhang; L Wang; Y Pu; H Zhang; Y He; Y Wang; Y Yu; T Yu; J Zhu

doi:10.1038/cddis.2014.367

The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression

Cell Death Dis. 2014 Sep 4;5(9):e1402. doi: 10.1038/cddis.2014.367.

Authors

L Lv¹, H Deng¹, Y Li², C Zhang³, X Liu⁴, Q Liu⁵, D Zhang⁶, L Wang¹, Y Pu¹, H Zhang⁷, Y He⁷, Y Wang⁸, Y Yu³, T Yu¹, J Zhu⁹

Affiliations

¹ Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China.
² Department of Biology, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, China.
³ Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
⁴ Department of Bioinformatics, MHBI (Shanghai) Biotech Inc., GuiPing Road 333, Building 4/104, Shanghai Juke Biotech Park, Shanghai, China.
⁵ School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China.
⁶ Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
⁷ Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China.
⁸ Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
⁹ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
Antineoplastic Agents, Phytogenic / therapeutic use
Antineoplastic Agents, Phytogenic / toxicity
Base Sequence
Cell Line, Tumor
Cell Survival / drug effects
DNA Damage
DNA Methylation*
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Humans
Kruppel-Like Transcription Factors / antagonists & inhibitors
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism*
Male
Mice
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / antagonists & inhibitors
MicroRNAs / genetics
MicroRNAs / metabolism*
Molecular Sequence Data
NF-kappa B / metabolism
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Oligonucleotides, Antisense / genetics
Oligonucleotides, Antisense / metabolism
Oxidative Stress
Plasminogen Activators / antagonists & inhibitors
Plasminogen Activators / genetics
Plasminogen Activators / metabolism*
Proto-Oncogene Proteins c-myc / metabolism
RNA Interference
RNA, Small Interfering / metabolism
Receptors, Notch / metabolism
Ribonucleoproteins / antagonists & inhibitors
Ribonucleoproteins / genetics
Ribonucleoproteins / metabolism*
Serine-Arginine Splicing Factors
Signal Transduction
Transplantation, Heterologous
Tumor Suppressor Proteins / antagonists & inhibitors
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Urinary Bladder Neoplasms / drug therapy
Urinary Bladder Neoplasms / metabolism
Urinary Bladder Neoplasms / pathology

Substances

3' Untranslated Regions
Antineoplastic Agents, Phytogenic
HIC2 protein, human
Kruppel-Like Transcription Factors
MIRN193 microRNA, human
MicroRNAs
NF-kappa B
Nuclear Proteins
Oligonucleotides, Antisense
Proto-Oncogene Proteins c-myc
RNA, Small Interfering
Receptors, Notch
Ribonucleoproteins
Tumor Suppressor Proteins
SRSF2 protein, human
Serine-Arginine Splicing Factors
Plasminogen Activators