Overexpression of the TGF-β antagonist Smad7 in endometrial cancer
Overexpression of the TGF-β antagonist Smad7 in endometrial cancer
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DOI：
10.1016/j.ygyno.2004.10.006
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发表时间：
2005-02-01
影响因子：
4.7
通讯作者：
Janknecht, R
中科院分区：
文献类型：
--
作者：
Dowdy, SC;Mariani, A;Janknecht, R
Objective.我们已经证明，HER 2/Neu可能激活子宫内膜癌，卵巢癌和乳腺癌细胞系中的Smad 7启动子。升高的Smad 7水平可以拮抗TGF-β通路，导致肿瘤监视和潜在癌症形成的减少。我们的目的是确定Smad 7是否真的在子宫内膜癌中过表达，以及Smad 7 RNA水平是否与肿瘤分级或临床终点相关。从16例1级疾病患者和23例3级疾病患者中获得速冻子宫内膜癌标本。另外，收集18例因良性适应症行子宫切除术患者的子宫内膜作为对照。提取RNA，进行实时荧光定量PCR检测Smad 7 RNA的表达水平。通过回顾性图表审查记录临床结果，包括复发时间。肿瘤组织中Smad 7的转录水平比对照组平均升高11倍以上（P < 0.001）。Smad 7 RNA在1级和3级肿瘤之间无显著差异。19例复发患者中，Smad 7低表达组中位复发时间为56.3个月，高表达组中位复发时间为30个月（P < 0.004）。与正常子宫内膜相比，Smad 7似乎在子宫内膜癌中上调。此外，Smad 7基因高表达与较短的复发时间相关。鉴于许多子宫内膜癌已被证明是TGF-β无反应的，Smad 7应作为恢复TGF-β反应性和限制肿瘤生长的潜在靶点进行研究。(C)2004年爱思唯尔公司All rights reserved.
Objective. We have shown that HER2/Neu may activate the Smad7 promoter in endometrial, ovarian, and breast cancer cell lines. Elevated Smad7 levels could then antagonize the TGF-beta pathway, leading to a reduction in tumor surveillance and potential cancer formation. Our aim was to determine if Smad7 was in fact overexpressed in endometrial cancers and whether Smad7 RNA levels correlated with tumor grade or clinical endpoints.Methods. Snap-frozen endometrial cancer specimens from 16 patients with grade 1 disease and 23 patients with grade 3 disease were obtained. Additionally, the endometrium from 18 patients who underwent hysterectomy for benign indications was collected as a control. RNA was extracted and Subjected to quantitative real-time PCR to determine the degree of Smad7 RNA expression. Clinical outcomes including time to recurrence were recorded through retrospective chart review.Results. Smad7 transcripts in the tumors were over 11-fold elevated on average than in controls ( P < 0.001). There was no significant difference in Smad7 RNA between grades 1 and 3 tumors. For the 19 patients who recurred, median time to recurrence was 56.3 months for those with low Smad7 expression versus 30 months for those with high Smad7 expression (P < 0.004).Conclusion. Smad7 appears to be upregulated in endometrial cancers compared to normal endometrium. Furthermore, high Smad7 gene expression was associated with a shorter time to recurrence. Given that many endometrial cancers have been shown to be TGF-beta-unresponsive, Smad7 should be investigated as a potential target to restore TGF-beta responsiveness and limit tumor growth. (C) 2004 Elsevier Inc. All rights reserved.