title: MiR-34a chemosensitizes bladder cancer cells to cisplatin treatment regardless of p53-Rb pathway status.
abstract: MiR-34a is a downstream effector of p53 that has been shown to target several molecules associated with cell cycle and cell survival pathways. As alterations in these pathways are frequent in muscle invasive transitional cell carcinoma of the bladder (MI-TCC), for example mutation or loss of p53 and Rb, the goal of this study was to determine whether manipulation of miR-34a expression levels could abrogate the effect of these alterations and sensitize bladder cancer cells to chemotherapy. We demonstrate that transfection of T24, TCCSUP and 5637 with pre-miR-34a followed by cisplatin treatment results in a dramatic reduction in clonogenic potential and induction of senescence compared to treatment with cisplatin alone. Molecular analyses identified Cdk6 and sirtuin (SIRT)-1 as being targeted by miR-34a in MI-TCC cells, however, inhibition of Cdk6 and SIRT-1 was not as effective as pre-miR-34a in mediating chemosensitization. Analysis of 27 preneoadjuvant chemotherapy patient samples revealed many of the patients who subsequently did not respond to treatment (based on surgical resection postchemotherapy and 5-year survival data) express lower levels of miR-34a, however, a statistically significant difference between the responder and nonresponder groups was not observed (p = 0.1174). Analysis of eight sets of pre- and postneoadjuvant chemotherapy patient samples determined miR-34a expression increased postchemotherapy in only two of the eight patients. The combined data indicate that elevation of miR-34a expression levels before chemotherapy would be of benefit to MI-TCC patients, particularly in a setting of low miR-34a expression.
authors.affiliation: Department of Urology, University of California, Davis, School of Medicine and Cancer Center, Sacramento, CA 95817, USA.
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Vinall
authors.forename: Alexandra Z
authors.initials: AZ
authors.lastname: Ripoll
authors.forename: Sisi
authors.initials: S
authors.lastname: Wang
authors.forename: Chong-Xian
authors.initials: CX
authors.lastname: Pan
authors.forename: Ralph W
authors.initials: RW
authors.lastname: deVere White
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000032:analysis / Q000502:physiology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D002945:Cisplatin