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

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。为明确子宫内膜癌(Em Ca)细胞鳞状分化(SQD)过程中的作用，我们检测了80例具有SQD区的Em Ca组织中β-连环蛋白、细胞周期蛋白D1、P53、p21WAF1和早幼粒细胞白血病(PML)的表达，并与Ki-67抗原阳性确定的细胞增殖进行了比较。β-连环蛋白-Tcf介导的转录的作用也通过Em-Ca细胞进行了检测。在临床病例中，β-连环蛋白在SQD区的核聚集较多见，与细胞周期蛋白D1、P53、p21WAF1的表达呈正相关，与Ki-67、PML的表达呈负相关。β-连环蛋白、细胞周期蛋白D1、P53和p21WAF1在SQD中的表达与癌旁病变显著相关。突变的β-连环蛋白稳定表达或受四环素调控后，细胞周期蛋白D1、p14ARF、p53和p21WAF1的表达水平增加，而PML表达水平无明显变化，β-连环蛋白-TCF4介导的转录激活由TOP/FOP决定。细胞形态呈衰老样，而不是鳞片状。此外，过表达的β-catenin可以激活p14ARF和细胞周期蛋白D1启动子的转录，且依赖于TCF4。这些结果表明，在子宫内膜癌中，核β-连环蛋白可以同时诱导p53-p21WAF1通路的激活和细胞周期蛋白D1的过度表达，从而抑制细胞增殖或诱导细胞衰老。然而，仅有β-catenin的过度表达不足以在EmCa细胞中形成鳞状表型，这表明核聚集是反式分化的初始信号。

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.