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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.

β-连环蛋白作为一种转录因子在多种肿瘤中的功能后果是复杂的。为了阐明子宫内膜癌（Em Ca）细胞鳞状分化（SqD）过程中的作用，我们研究了80例Em Ca中β-catenin、cyclin D1、p53、p21 WAF 1和PML（早幼粒细胞白血病）的表达，并与Ki-67抗原阳性的细胞增殖进行比较。还使用Em Ca细胞检查β-连环蛋白-TCF介导的转录的作用。在临床病例中，β-catenin在SqD区的核内积聚更频繁，与cyclin D1、p53和p21 WAF 1的表达呈正相关，与Ki-67和PML免疫反应性呈负相关。细胞核β-catenin、cyclin D1、p53和p21 WAF 1在SqD与癌旁组织中表达显著相关。石川细胞系具有稳定的或四环素调节的突变型β-连环蛋白表达，显示细胞周期蛋白D1、p14 ARF、p53和p21 WAF 1的表达水平增加，但不显示PML和由TOP/FOP构建体确定的β-连环蛋白-TCF 4介导的转录激活。细胞形态为衰老样而非鳞状。此外，过表达的β-catenin可以激活p14 ARF和cyclin D1启动子的转录，并以TCF 4依赖的方式。这些发现表明，在Em Cas中，核β-catenin可以同时诱导p53-p21 WAF 1通路的激活和cyclin D1的过表达，从而导致细胞增殖抑制或诱导细胞衰老。然而，单独的β-连环蛋白的过表达不足以在Em Ca细胞中形成鳞状细胞表型，这表明核积累是转分化的初始信号。