Bandapalli Obul R, Dihlmann Susanne, Helwa Reham, Macher-Goeppinger Stephan, Weitz Jurgen, Schirmacher Peter, Brand Karsten
Department of General Pathology, University of Heidelberg, Germany.
J Pathol. 2009 Jul;218(3):370-9. doi: 10.1002/path.2539.
beta-Catenin is a pivotal molecule of the Wnt-signalling pathway, involved in regulation of developmental and oncogenic processes as well as in intercellular adhesion. So far, beta-catenin has been thought to be regulated mainly at the protein level. Here, we provide evidence for a transcriptional mechanism of beta-catenin regulation at the invasion front of colorectal liver metastases. In a nude mouse/LS174T cell xenograft model of colorectal liver metastases, we observed beta-catenin up-regulation at the mRNA and protein levels and a 13.7-fold increase of beta-catenin promoter activity in the cancer cells of the invasion front. In addition, the promoter activity was five-fold higher in the interior of the tumour than in cells growing in cell culture. In vitro studies revealed binding of TCF-4 to the beta-catenin promoter and reduced promoter activity by over-expression of dominant negative TCF-4, or beta-catenin knock-down and increased activity by beta-catenin over-expression, indicating that beta-catenin acts as co-transcription factor of its own promoter. In 55% (7/13) of clinical specimens, beta-catenin mRNA was markedly elevated in the cancer cells of the invasion front. Elevation of mRNA was paralleled by increased nuclear and cytoplasmic beta-catenin protein concentrations. These data indicate that transcriptional regulation contributes to the dynamic changes of beta-catenin levels upon the confrontation of tumour cells with the host microenvironment.
β-连环蛋白是Wnt信号通路的关键分子，参与发育和致癌过程的调控以及细胞间黏附。到目前为止，β-连环蛋白一直被认为主要在蛋白质水平受到调控。在此，我们提供证据表明在结直肠癌肝转移灶的侵袭前沿存在β-连环蛋白的转录调控机制。在结直肠癌肝转移的裸鼠/LS174T细胞异种移植模型中，我们观察到侵袭前沿癌细胞中β-连环蛋白在mRNA和蛋白质水平上调，且β-连环蛋白启动子活性增加了13.7倍。此外，肿瘤内部的启动子活性比细胞培养中生长的细胞高5倍。体外研究显示TCF-4与β-连环蛋白启动子结合，过表达显性负性TCF-4可降低启动子活性，或敲低β-连环蛋白可降低启动子活性，而过表达β-连环蛋白则增加启动子活性，这表明β-连环蛋白作为其自身启动子的共转录因子发挥作用。在55%（7/13）的临床标本中，侵袭前沿癌细胞中的β-连环蛋白mRNA明显升高。mRNA升高的同时，细胞核和细胞质中的β-连环蛋白蛋白浓度也增加。这些数据表明转录调控有助于肿瘤细胞与宿主微环境相互作用时β-连环蛋白水平的动态变化。
