title: microRNA response elements-regulated TRAIL expression shows specific survival-suppressing activity on bladder cancer.
abstract: BACKGROUND
  Bladder transitional cell carcinoma greatly threatens human health all over the world. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows a strong apoptosis-inducing effect on a variety of cancer cells including bladder cancer. However, adenovirus-mediated TRAIL expression still showed cytotoxicity to normal cells mainly due to lack of tumor specificity.
  
  
  METHODS
  To solve the problem, we applied miRNA response elements (MREs) of miR-1, miR-133 and miR-218 to confer TRAIL expression with specificity to bladder cancer cells.
  
  
  RESULTS
  Expression of miR-1, miR-133 and miR-218 was greatly decreased in bladder cancer than normal bladder tissue. Luciferase assay showed that application of the 3 MREs was able to restrain exogenous gene expression to within bladder cancer cells. Subsequently, we constructed a recombinant adenovirus with TRAIL expression regulated by MREs of miR-1, miR-133 and miR-218, namely Ad-TRAIL-MRE-1-133-218. qPCR, immunoblotting and ELISA assays demonstrated that Ad-TRAIL-MRE-1-133-218 expressed in bladder cancer cells, rather than normal bladder cells. The differential TRAIL expression also led to selective apoptosis-inducing and growth-inhibiting effect of Ad-TRAIL-MRE-1-133-218 on bladder cancers. Finally, bladder cancer xenograft in mouse models further confirmed that Ad-TRAIL-MRE-1-133-218 effectively suppressed the growth of bladder cancers.
  
  
  CONCLUSIONS
  Collectively, we demonstrated that MREs-based TRAIL delivery into bladder cancer cells was feasible and efficient for cancer gene therapy.
authors: Department of Urology, General Hospital of Chengdu Military Area Command of Chinese PLA, Chengdu 610083, Sichuan Province, PR China. zhaoyg717@163.com
authors: Youguang
authors: Y
authors: Zhao
authors: Ying
authors: Y
authors: Li
authors: Liang
authors: L
authors: Wang
authors: Hang
authors: H
authors: Yang
authors: Qingtang
authors: Q
authors: Wang
authors: Haiyan
authors: H
authors: Qi
authors: Shadan
authors: S
authors: Li
authors: Peng
authors: P
authors: Zhou
authors: Ping
authors: P
authors: Liang
authors: Qiwu
authors: Q
authors: Wang
authors: Xiaowei
authors: X
authors: Li
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002470:Cell Survival / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D020218:Response Elements; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: C544547:MIRN1 microRNA, human; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human