Integrative transcriptomics-based identification of cryptic drivers of taxol-resistance genes in ovarian carcinoma cells: Analysis of the androgen receptor.
Integrative transcriptomics-based identification of cryptic drivers of taxol-resistance genes in ovarian carcinoma cells: Analysis of the androgen receptor.
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DOI：
10.18632/oncotarget.4824
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发表时间：
2015-09-29
期刊：
影响因子：
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通讯作者：
Chao CC
中科院分区：
文献类型：
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作者：
Sun NK;Huang SL;Lu HP;Chang TC;Chao CC
对紫杉醇耐药（txr）相关基因的系统分析从未进行过。在本研究中，我们建立了txr卵巢癌细胞系，以鉴定与化疗耐药有关的基因。转录组分析显示，txr细胞中有1194个过表达基因。在上调的基因中，使用MetaCore分析鉴定了12个以上的隐性转录因子（包括AR、C/EBPβ、ERα、HNF4α、C - jun /AP-1、C - myc和SP-1）。值得注意的是，单独沉默这些转录因子（HNF4 '除外）会使txr细胞对紫杉醇敏感。选择雄激素受体（AR）及其靶基因进行进一步分析。使用RNA干扰沉默AR在txr细胞中产生了3倍的紫杉醇敏化，这种反应与沉默abcb1产生的反应相似。AR沉默也下调了重要的txr候选基因的表达（包括abcb1、abcb6、abcg2、bmp5、fat3、fgfr2、h1f0、srcrb4d和tmprss15）。相反，使用激动剂DHT激活AR可上调靶基因的表达。单独沉默9个ar调节的txr基因中的7个（78%）使txr细胞对紫杉醇敏感。使用化学抑制剂抑制AKT和JNK细胞激酶可显著抑制AR表达。这些结果表明，AR是与txr相关的基因表达的关键驱动因素。
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.