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-连环蛋白作为转录因子的功能在多种肿瘤中是复杂的。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 β-连环蛋白以及细胞周期蛋白 D1 的表达。 80 例具有 SqD 区域的 Em Ca 中的 p53、p21WAF1 和 PML（早幼粒细胞白血病），与参照 Ki-67 抗原测定的细胞增殖进行比较在临床病例中，β-连环蛋白-TCF 介导的转录的作用在 SqD 区域更频繁，与细胞周期蛋白 D1、p53 和 p21WAF1 的表达呈正相关。，并且与 Ki-67 和 PML 免疫反应性成反比，注意到核 β-连环蛋白、细胞周期蛋白 D1、p53 和 p21WAF1 之间存在显着相关性。 SqD 和周围癌病变具有稳定或四环素调节的突变 β-连环蛋白表达，显示细胞周期蛋白 D1、p14ARF、p53 和 p21WAF1 的表达水平增加，但 PML 和 β-连环蛋白的激活没有增加。 -由 TOP/FOP 构建体确定的 TCF4 介导的转录细胞形态呈衰老样而不是鳞状，而且β-连环蛋白过度表达。可以以 TCF4 依赖性方式激活 p14ARF 和细胞周期蛋白 D1 启动子的转录。这些发现表明，在 Em Cas 中，核 β-catenin 可以同时诱导 p53-p21WAF1 通路的激活和细胞周期蛋白 D1 的过度表达，从而抑制细胞。然而，仅β-连环蛋白的过度表达不足以在 Em Ca 细胞中形成鳞状细胞表型，这表明核积累是细胞衰老的初始信号。转分化。