title: Cisplatin-induced epigenetic activation of miR-34a sensitizes bladder cancer cells to chemotherapy.
abstract: BACKGROUND
  Accumulating evidence suggests a tumor suppressive role for miR-34a in human carcinogenesis. However, its precise biological role remains largely elusive. This study aimed to reveal the association of the miR-34a expression and its modulation of sensitivity to cisplatin in muscle-invasive bladder cancer (MIBC).
  
  
  METHODS
  miR-34a expression in MIBC cell lines and patient tissues was investigated using qPCR. The methylation analysis of miR-34a promoter region was performed by MassARRAY. Synthetic short single or double stranded RNA oligonucleotides and lentiviral vector were used to regulate miR-34a expression in MIBC cells to investigate its function in vitro and in vivo.
  
  
  RESULTS
  miR-34a expression was frequently decreased in MIBC tissues and cell lines through promoter hypermethylation while it was epigenetically increased in MIBC cells following cisplatin treatment. Increased miR-34a expression significantly sensitized MIBC cells to cisplatin and inhibited the tumorigenicity and proliferation of cancer cells in vitro and in vivo. Furthermore, we identified CD44 as being targeted by miR-34a in MIBC cells following cisplatin treatment, and increased CD44 expression could efficiently reverse the effect of miR-34a on MIBC cell proliferation, colongenic potential and chemosensitivity.
  
  
  CONCLUSIONS
  Cisplatin-based chemotherapy induced demethylation of miR-34a promoter and increased miR-34a expression, which in turn sensitized MIBC cells to cisplatin and decreased the tumorigenicity and proliferation of cancer cells that by reducing the production of CD44.
authors.forename: Heng
authors.initials: H
authors.lastname: Li
authors.forename: Gan
authors.initials: G
authors.lastname: Yu
authors.forename: Runlin
authors.initials: R
authors.lastname: Shi
authors.forename: Bin
authors.initials: B
authors.lastname: Lang
authors.forename: Xianguo
authors.initials: X
authors.lastname: Chen
authors.forename: Ding
authors.initials: D
authors.lastname: Xia
authors.forename: Haibing
authors.initials: H
authors.lastname: Xiao
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Guo
authors.forename: Wei
authors.initials: W
authors.lastname: Guan
authors.forename: Zhangqun
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. xiaowei0041@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D002945:Cisplatin