The Tumor-Suppressive Function of UNC5D and Its Repressed Expression in Renal Cell Carcinoma
The Tumor-Suppressive Function of UNC5D and Its Repressed Expression in Renal Cell Carcinoma
复制标题
DOI：
10.1158/1078-0432.ccr-12-2978
复制
发表时间：
2013-06-01
影响因子：
11.5
通讯作者：
Zhang, Jun
中科院分区：
文献类型：
--
作者：
Lu, Dan;Dong, Dong;Zhang, Jun
目的：作为UNC 5 H受体的新成员，UNC 5D/H4在肿瘤发生中的作用尚不清楚。本研究的目的是检测UNC 5D在原发性肾细胞癌（RCC）中的表达，分析其在RCC中下调的机制，并评估其与肿瘤生长和迁移的功能相关性。实验设计：收集了44对原发性肾细胞癌和相应的邻近非癌组织。通过逆转录酶-PCR、实时PCR或免疫组织化学评估UNC 5D的mRNA和蛋白表达水平。还分析了UNC 5D启动子的表观遗传学改变和UNC 5D基因座的洛缺失。结果：UNC 5D在包括肾癌细胞在内的多种肿瘤细胞系中的表达均明显减弱，差异有统计学意义（P < 0. 05）。与配对的相邻非癌组织相比，在原发性RCC组织中也观察到类似的减少。甲基化特异性PCR显示UNC 5D启动子在显著比例（40.9%）的肿瘤组织（18/44）中存在高甲基化。44例RCC患者中有13例（29.5%）观察到UNC 5D的洛杂合性缺失（LOH）。恢复UNC 5D在肾癌细胞中的表达显著抑制细胞增殖、锚定依赖性和非依赖性生长以及迁移和侵袭，而UNC 5D的敲低促进细胞生长。结论：UNC 5D是一种功能性肿瘤抑制因子，在RCC中由于启动子甲基化和洛缺失而下调。(c)2013年AACR。
Purpose: As a newly added member of the UNC5H receptors, the function of UNC5D/H4 in tumorigenesis remains poorly defined. The aim of this study was to examine the expression of UNC5D in primary renal cell carcinomas (RCC), analyze the mechanisms responsible for its downregulation in RCC, and assess its functional relevance to tumor growth and migration.Experimental Design: Forty-four paired primary RCCs and corresponding adjacent noncancerous tissues were collected. The mRNA and protein expression level of UNC5D was assessed by reverse transcriptase-PCR, real-time PCR, or immunohistochemistry. Epigenetic alterations in UNC5D promoter and LOH in the UNC5D locus were also analyzed. Ectopic expression of UNC5D in renal cancer cells with silenced expression of UNC5D was used for analysis of the biologic functions of UNC5D.Results: UNC5D expression was attenuated in multiple carcinoma cell lines including renal cancer cells. Similar reduction was also observed in primary RCC tissues as compared with paired adjacent noncancerous tissues. Methylation-specific PCR showed hypermethylation in UNC5D promoter in a significant proportion (18 of 44) of tumor tissue (40.9%). LOH of UNC5D was observed in 13 of 44 patients with RCCs (29.5%). Restoration of UNC5D expression in renal cancer cells significantly inhibited cell proliferation, anchorage-dependent and -independent growth, as well as migration and invasion, whereas knockdown of UNC5D promoted cell growth. Furthermore, ectopic expression of UNC5D induced G(2)-M cell-cycle arrest.Conclusions: UNC5D is a functional tumor suppressor that is frequently downregulated in RCCs due to promoter hypermethylation and LOH. (c) 2013 AACR.