title: Contributions of microRNA dysregulation to cisplatin resistance in adenocarcinoma cells.
abstract: Cisplatin resistance in cancer cells is due to a pleiotropic phenotype transition that allows cells to resist cell death. miRNAs have been shown to be reliable markers of phenotype, critical in cell differentiation, and dysregulated in cancer and other pathologies. Here we investigate the influence of miRNA on cisplatin resistance in KB adenocarcinoma cells. Silencing both DICER and TRBP2 in the miRNA biosynthesis pathway in KB-3-1 (sensitive parental), KB-CP.5 (cisplatin-resistant), and KB-CP20 (highly cisplatin-resistant) cells resulted in the reversal of cisplatin resistance, with no effect on cell viability in the absence of cisplatin. We found miR-181 expression differences in the cell lines using RT-PCR, with several members of the miR-181 family overexpressed in two KB cisplatin-resistant lines and in two cisplatin-resistant lung cancer lines, compared to their respective parental cells. Functional assays showed minimal effects of miR-181 on cisplatin resistance. We conclude that the miRNA biosynthesis pathway is critical for maintaining the cisplatin-resistant phenotype, but that it is difficult to determine the precise miRNAs involved in cisplatin resistance simply using expression profiles of individual miRNA species. Functional assays are needed to determine the influence of a specific miRNA and different members of the same miRNA family may have opposite effects.
authors.affiliation: Department of Microbiology and Immunology, Georgetown University, Washington, DC, USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Pouliot
authors.forename: Ding-Wu
authors.initials: DW
authors.lastname: Shen
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D043244:Ribonuclease III / Q000037:antagonists & inhibitors / Q000235:genetics; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000099253:Trans-Activation Responsive RNA-Binding Protein
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D053487:DEAD-box RNA Helicases; D035683:MicroRNAs; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D043244:Ribonuclease III; D000099253:Trans-Activation Responsive RNA-Binding Protein; C408087:DICER1 protein, human