Increased nucleotide polymorphic changes in the 5'-untranslated region of delta-catenin (CTNND2) gene in prostate cancer.
Increased nucleotide polymorphic changes in the 5'-untranslated region of delta-catenin (CTNND2) gene in prostate cancer.
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DOI：
10.1038/onc.2008.399
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发表时间：
2009-01-29
期刊：
影响因子：
8
通讯作者：
Lu, Q.
中科院分区：
文献类型：
--
作者：
Wang, T.;Chen, Y-H;Hong, H.;Zeng, Y.;Zhang, J.;Lu, J-P;Jeansonne, B.;Lu, Q.
关键词：
癌症的发病机制涉及多种遗传和表观遗传改变，导致基因表达的致癌改变。δ-连环蛋白(CTNND2)在肿瘤中高表达，尽管其上调的机制差异很大。在此，我们报告在前列腺癌中，δ-连环蛋白启动子中CpG岛的甲基化不是一个主要的调控事件。也未发现δ-连环蛋白基因扩增。然而，通过单链构象多态性分析，我们观察到前列腺癌组织中δ-连环蛋白基因5‘-非翻译区核苷酸水平的变化。至少有一个这样的改变(-9G>；A)是与高Gleason评分、低分化前列腺癌相关的真正的体细胞点突变。激光捕获显微切割结合聚合酶链式反应分析只在癌组织中检测到突变，而在邻近的良性前列腺组织中没有检测到突变。利用编码荧光素酶报告基因的嵌合基因，我们发现这种突变，而不是随机突变或破坏上游开放阅读框架的突变，导致了显著更高的表达和酶活性。这种突变不影响转录效率，表明它促进了δ-连环蛋白的翻译。这是δ-连环蛋白基因突变在癌症中的首次报道，支持多种机制导致其在癌变过程中表达增加的观点。
Cancer pathogenesis involves multiple genetic and epigenetic alterations, which result in oncogenic changes in gene expression. δ-Catenin (CTNND2) is overexpressed in cancer although the mechanisms of its upregulation are highly variable. Here we report that in prostate cancer the methylation of CpG islands in δ-catenin promoter was not a primary regulatory event. There was also no δ-catenin gene amplification. However, using Single-Strand Conformation Polymorphism analysis, we observed the increased nucleotide changes in the 5′-untranslated region of δ-catenin gene in human prostate cancer. At least one such change (-9 G>A) is a true somatic point mutation associated with a high Gleason score, poorly differentiated prostatic adenocarcinoma. Laser capture microdissection coupled with PCR analyses detected the mutation only in cancerous but not in the adjacent benign prostatic tissues. Using chimeric genes encoding the luciferase reporter, we found that this mutation, but not a random mutation or a mutation that disrupts an upstream open reading frame, resulted in a remarkably higher expression and enzyme activity. This mutation did not affect transcriptional efficiency, suggesting that it promotes δ-catenin translation. This is the first report of δ-catenin gene mutation in cancer and supports the notion that multiple mechanisms contribute to its increased expression in carcinogenesis.
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影响因子：
8
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1016/j.bbrc.2008.02.069
发表时间：
2008-05-02
影响因子：
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作者：
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通讯作者：
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