A role of beta-catenin/p53 pathway on tumor cell proliferation and differenatiation of endometrial carcinoma cells

β-catenin/p53通路对子宫内膜癌细胞增殖和分化的作用

基本信息

批准号：
15590313
负责人：
SAEGUSA Makoto
金额：
$ 2.05万
依托单位：
Kitasato University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590313/
关键词：
Beta-catenin p53 p21WAF1 p14ARF endometrial cancer senescence β-カテニン子宮内膜癌 p21 p14 TCF4

项目摘要

The functional consequences of β-catenin as a transcription factor are complex in a variety of tumors. To clarify roles during squamous differentiation (SqD) of endometrial carcinoma (Em Ca) cells, we investigated expression of β-catenin, as well as cyclin D1, p53, p21WAF1, and PML (promyelocytic leukemia) in 80 cases of Em Ca with SqD areas, in comparison with cell proliferation determined with reference to Ki-67 antigen positivity. The role of β-catenin-TCF-mediated transcription was also examined using Em Ca cells. In clinical cases, nuclear β-catenin accumulation was more frequent in SqD areas, being positively linked with expression of cyclin D1, p53, and p21WAF1, and inversely to Ki-67 and PML immunoreactivity. Significant correlations of nuclear β-catenin, cyclin D1, p53, and p21WAF1, were noted between SqD and the surrounding carcinoma lesions. The Ishikawa cell line, with stable or tetracycline-regulated expression of mutant β-catenin, showed an increase in expression levels of cyclin D1, p14ARF, p53, and p21WAF1 but not PML and activation of β-catenin-TCF4-mediated transcription determined by TOP/FOP constructs. The cell morphology was senescence-like rather than squamoid in appearance. Moreover, overexpressed β-catenin could activate transcription from p14ARF and cyclin D1 promoters, in a TCF4-dependent manner. These findings indicate that in Em Cas, nuclear β-catenin can simultaneously induce activation of the p53-p21WAF1 pathway and overexpression of cyclin D1, leading to suppression of cell proliferation or induction of cell senescence. However, overexpression of β-catenin alone is not sufficient for development of a squamoid phenotype in Em Ca cells, suggesting that nuclear accumulation is an initial signal for trans-differentiation.

在多种肿瘤中，β-catenin作为转录因子的功能后果是复杂的。为了阐明子宫内膜癌（EM CA）细胞的鳞状分化（SQD）的作用，我们研究了80例与SQD区域的Cy-Ca ploliferigs相比，我们研究了80例EM CA的表达，Cyclin d1，p53，p21Waf1和PML（Promyelodictic Leukemia）（Promyelodictic Leukemia）在80例中，并在Cell Plorifsigs plolifsigs中进行了分析。还使用EM CA细胞检查了β-catenin-TCF介导的转录的作用。在临床情况下，在SQD区域中，核β-catenin的积累频率更高，与细胞周期蛋白D1，p53和P21WAF1的表达正相关，并与KI-67和PML免疫反应性成反。在SQD和周围的癌病变之间发现了核β-catenin，Cyclin D1，P53和P21WAF1的显着相关性。 Ishikawa细胞系具有突变体β-catenin的稳定或四环素调节的表达，显示细胞周期蛋白D1，p14arf，p53和p21WAF1的表达水平升高，但不是PML，而不是激活β-catenin-tcf4-tcf4-tcf4介导的转录，由TOP/FOP构造确定。细胞的形态在外观上是感应的，而不是鳞状的。此外，过表达的β-catenin可以以TCF4依赖性方式激活P14ARF和Cyclin D1启动子的转录。这些发现表明，在EM CAS中，核β-catenin可以简单地诱导p53-P21WAF1途径的激活和细胞周期蛋白D1的过表达，从而导致细胞增殖或诱导细胞感应。然而，单独的β-catenin的过表达不足以在EM CA细胞中发展平方表型，这表明核积累是反差异的初始信号。