Résumé
Ovarian cancer is the leading cause of death in women worldwide. Cisplatin is the core of first-line chemotherapy for patients with advanced ovarian cancer. Many patients eventually become resistant to cisplatin, diminishing its therapeutic effect. MicroRNAs (miRNAs) have critical functions in diverse biological processes. Using miRNA profiling and polymerase chain reaction validation, we identified a panel of differentially expressed miRNAs and their potential targets in cisplatin-resistant SKOV3/DDP ovarian cancer cells relative to cisplatin-sensitive SKOV3 parental cells. More specifically, our results revealed significant changes in the expression of 13 of 663 miRNAs analyzed, including 11 that were up-regulated and 2 that were down-regulated in SKOV3/DDP cells with or without cisplatin treatment compared with SKOV3 cells with or without cisplatin treatment. miRNA array and mRNA array data were further analyzed using Ingenuity Pathway Analysis software. Bioinformatics analysis suggests that the genes ANKRD17, SMC1A, SUMO1, GTF2H1, and TP73, which are involved in DNA damage signaling pathways, are potential targets of miRNAs in promoting cisplatin resistance. This study highlights candidate miRNA-mRNA interactions that may contribute to cisplatin resistance in ovarian cancer.
Sujets)
Femelle , Humains , Protéines du cycle cellulaire , Lignée cellulaire tumorale , Protéines chromosomiques nonhistones , Cisplatine , Cysteine endopeptidases , Protéines de liaison à l'ADN , Régulation négative , Résistance aux médicaments antinéoplasiques , Endopeptidases , microARN , Protéines nucléaires , Tumeurs de l'ovaire , Phosphoprotéines , ARN messager , Transduction du signal , Facteurs de transcription TFII , Protéine tumorale p73 , Protéines suppresseurs de tumeurs , Régulation positiveRésumé
Over the last decade, great progress has been made in elucidating how the human genome operates in the chromatin context. This paper describes our work on two human acetyltransferases, PCAF and TIP60, and their interaction partners. This study provides new clues on the function of these enzymes. In a striking parallel with the general transcription factor TFIID, PCAF complex contains proteins that have histone-like domains. We speculate that these subunits can presumably form a nucleosome-like structure on DNA, which would allow PCAF to contribute to the maintenance of an active state of chromatin. On the other hand, TIP60 complex contains two eukaryotic homologs of bacterial RuvB helicase/ATPse, involved in recombination and repair. Accordingly, expression of a dominant negative mutant of TIP60 in living cells interferes with their ability to repair DNA damage, which points out, for the first time, a role for a histone acetyltransferase in a process other than transcription. We also have evidence implicating TIP60 in the apoptotic response to DNA damage.