Integrative transcriptomics-based identification of cryptic drivers of taxol-resistance genes in ovarian carcinoma cells: Analysis of the androgen receptor
| Autor: | Chuck C.-K. Chao, Shang-Lang Huang, Ting-Chang Chang, Nian-Kang Sun, Hsing-Pang Lu |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Paclitaxel Cell Survival Oligonucleotides Biology Polymerase Chain Reaction Transcriptome Inhibitory Concentration 50 RNA interference androgen receptor Cell Line Tumor Gene expression Humans Gene silencing Gene Silencing Transcription factor transcription factor Oligonucleotide Array Sequence Analysis Ovarian Neoplasms Regulation of gene expression taxol Gene Expression Profiling Carcinoma Prostatic Neoplasms Antineoplastic Agents Phytogenic Molecular biology Up-Regulation Gene Expression Regulation Neoplastic Androgen receptor Gene expression profiling ovarian cancer Phenotype Gene Expression Regulation Oncology Drug Resistance Neoplasm Receptors Androgen Cancer research Female RNA Interference multiple drug resistance Research Paper Transcription Factors |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.4824 |
| Popis: | A systematic analysis of the genes involved in taxol resistance (txr) has never been performed. In the present study, we created txr ovarian carcinoma cell lines to identify the genes involved in chemoresistance. Transcriptome analysis revealed 1,194 overexpressed genes in txr cells. Among the upregulated genes, more than 12 cryptic transcription factors were identified using MetaCore analysis (including AR, C/EBPβ, ERα, HNF4α, c-Jun/AP-1, c-Myc, and SP-1). Notably, individual silencing of these transcription factors (except HNF4`)sensitized txr cells to taxol. The androgen receptor (AR) and its target genes were selected for further analysis. Silencing AR using RNA interference produced a 3-fold sensitization to taxol in txr cells, a response similar to that produced by silencing abcb1. AR silencing also downregulated the expression of prominent txr gene candidates (including abcb1, abcb6, abcg2, bmp5, fat3, fgfr2, h1f0, srcrb4d, and tmprss15). In contrast, AR activation using the agonist DHT upregulated expression of the target genes. Individually silencing seven out of nine (78%) AR-regulated txr genes sensitized txr cells to taxol. Inhibition of AKT and JNK cellular kinases using chemical inhibitors caused a dramatic suppression of AR expression. These results indicate that the AR represents a critical driver of gene expression involved in txr. |
| Databáze: | OpenAIRE |
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