Smad4 deffiency in cervical carcinoma cells
Smad4 deffiency in cervical carcinoma cells
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DOI：
10.1038/sj.onc.1208235
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发表时间：
2005-01-27
期刊：
影响因子：
8
通讯作者：
Schwarte-Waldhoff, I
中科院分区：
文献类型：
--
作者：
Baldus, SE;Schwarz, E;Schwarte-Waldhoff, I
子宫颈鳞状细胞癌是影响全世界妇女的最常见癌症之一。宫颈癌由宫颈上皮内病变引起，其中感染高危型人乳头瘤病毒通过病毒E6和E7癌蛋白的作用导致生长控制失调。肿瘤侵袭性生长的分子机制还知之甚少。然而，一个重要特征是通过转化生长因子β（TGF-β）摆脱生长抑制。染色体臂18 q的丢失是宫颈癌中最常见的细胞遗传学改变之一，并且与不良预后相关。由于TGF-β反应是由Smad蛋白介导的，并且肿瘤抑制基因Smad 4位于18 q21，我们分析了细胞系和原发癌中宫颈癌相关改变的Smad 4基因。在这里，我们报告Smad 4缺陷的13个宫颈癌细胞系，这是由于内含子重排或30个外显子的缺失。然而，所有的细胞系，无论其Smad 4状态，显示出对TGF-β的反应性缺失或中等。在41例原发性宫颈鳞癌中，10例Smad 4蛋白表达缺失，26例Smad 4蛋白表达降低。总之，我们的研究结果强烈表明，Smad 4基因的改变参与宫颈癌的发生。
Squamous cell carcinoma of the uterine cervix is one of the most frequent cancers affecting women worldwide. Carcinomas arise from cervical intraepithelial lesions, in which infection with high-risk human papillomavirus types has led to deregulated growth control through the actions of the viral E6 and E7 oncoproteins. The molecular mechanisms underlying progression to invasive tumor growth are poorly understood. One important feature, however, is the escape from growth inhibition by transforming growth factor beta (TGF-beta). Loss of chromosomal arm 18q is among the most frequent cytogenetic alterations in cervical cancers and has been associated with poor prognosis. Since the TGF-beta response is mediated by Smad proteins and the tumor suppressor gene Smad4 resides at 18q21, we have analysed the Smad4 gene for cervical cancer-associated alterations in cell lines and primary carcinomas. Here, we report Smad4 deficiency in four out of 13 cervical cancer cell lines which is due to an intronic rearrangement or deletions of 30 exons. All cell lines, however, showed either absent or moderate responsiveness to TGF-beta irrespective of their Smad4 status. In 41 primary squamous cervical carcinomas analysed, 10 samples showed loss of Smad4 protein expression and 26 samples a reduced expression. Altogether, our results strongly suggest that Smad4 gene alterations are involved in cervical carcinogenesis.