Expression profiling identifies altered expression of genes that contribute to the inhibition of transforming growth factor-β signaling in ovarian cancer
Expression profiling identifies altered expression of genes that contribute to the inhibition of transforming growth factor-β signaling in ovarian cancer
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DOI：
10.1158/0008-5472.can-06-0683
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发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Birrer, Michael J.
中科院分区：
文献类型：
--
作者：
Sunde, Jan S.;Donninger, Howard;Birrer, Michael J.
卵巢癌对转化生长因子-β（TGF-β）的抗增殖作用具有抗性;然而，这种抗性的机制仍不清楚。我们使用寡核苷酸阵列分析了37例未解剖的、68例显微解剖的晚期乳头状浆液性癌和14例显微解剖的早期乳头状浆液性癌，以确定参与卵巢癌的信号通路。与正常卵巢表面上皮细胞相比，共有7个参与TGF-β信号传导的基因在卵巢癌标本中的表达改变> 1.5倍（P < 0.001）。这些基因的表达被协同改变：抑制TGF-β信号传导的基因（DACH 1，BMP 7和EVI 1）在晚期卵巢癌中上调，相反，与正常样本相比，增强TGF-β信号传导的基因（PCAF，TFE 3，TGFBRII和SMAD 4）下调。DACH 1和EVI 1的微阵列数据进行了验证，使用定量实时PCR对22个显微切割卵巢癌标本。EVI 1基因位点在43%的肿瘤中扩增，基因拷贝数与EVI 1基因表达之间存在显著相关性（P = 0.029）。在所有样品中均未发现DACH 1基因座扩增。DACH 1和EVI 1抑制永生化正常卵巢上皮细胞中的TGF-β信号传导，而显性阴性DACH 1，DACH 1-Delta DS，部分恢复了对TGF-β耐药的卵巢癌细胞系中的信号传导。这些结果表明，这些基因的表达改变是导致卵巢癌中TGF-β信号传导中断的原因，它们可能是卵巢癌新的和新颖的治疗靶点。
Ovarian cancer is resistant to the antiproliferative effects of transforming growth factor-beta (TGF-beta); however, the mechanism of this resistance remains unclear. We used oligonucleotide arrays to profile 37 undissected, 68 microdissected advanced-stage, and 14 microdissected early-stage papillary serous cancers to identify signaling pathways involved in ovarian cancer. A total of seven genes involved in TGF-beta signaling were identified that had altered expression > 1.5-fold (P < 0.001) in the ovarian cancer specimens compared with normal ovarian surface epithelium. The expression of these genes was coordinately altered: genes that inhibit TGF-beta signaling (DACH1, BMP7, and EVI1) were up-regulated in advanced-stage ovarian cancers and, conversely, genes that enhance TGF-beta signaling (PCAF, TFE3, TGFBRII, and SMAD4) were down-regulated compared with the normal samples. The microarray data for DACH1 and EVI1 were validated using quantitative real-time PCR on 22 microdissected ovarian cancer specimens. The EVI1 gene locus was amplified in 43% of the tumors, and there was a significant correlation (P = 0.029) between gene copy number and EVI1 gene expression. No amplification at the DACH1 locus was found in any of the samples. DACH1 and EVI1 inhibited TGF-beta signaling in immortalized normal ovarian epithelial cells, and a dominant-negative DACH1, DACH1-Delta DS, partially restored signaling in an ovarian cancer cell line resistant to TGF-beta. These results suggest that altered expression of these genes is responsible for disrupted TGF-beta signaling in ovarian cancer and they may be useful as new and novel therapeutic targets for ovarian cancer.