Implication of intercellular adhesion in cancer invasion and metastasis

本系列研究的目的是阐明E-cadherin及其相关蛋白表达紊乱在肿瘤侵袭转移中的意义。1）E-cadherin表达降低的机制。在培养的癌细胞系中，未检测到E-钙粘蛋白基因的异常。有一株细胞虽然有E-cadherin的mRNA，但不表达E-cadherin蛋白，这可能是E-cadherin蛋白的转录后调控机制。2）E-cadherin的蛋白水解降解。我们发现，在癌组织中产生了一种降解形式的E-钙粘蛋白，逃逸到血液中，因此，在癌症患者的血清中检测到高水平。由于60%以上的胃癌患者血清E-cadherin水平较高，其作为肿瘤标志物的临床应用前景广阔。血清E-cadherin水平高的肿瘤细胞表面E-cadherin含量低。因此，蛋白酶的降解可能解释了体内E-钙粘蛋白的减少。3）β-连环蛋白对E-钙粘蛋白功能的调节。在癌细胞系和组织中，我们检测到β-连环蛋白的减少和/或酪氨酸磷酸化，这导致细胞间粘附的下降。EGF可诱导β-连环蛋白的酪氨酸磷酸化。4）E-钙粘蛋白对紧密连接形成的调节。封闭蛋白，一个主要的紧密连接蛋白，直接与导管的形成。由于E-cadherin是occludin表达所必需的，因此E-cadherin通过occludin的表达在分化调控中起重要作用。5）β-catenin参与APC的信号转导。有趣的是，不仅在结直肠癌中，而且在很少观察到APC突变的食管癌中，胞浆β-Catenin也积聚。

The purpose of this series of study is to elucidate the implication of disorder of E-cadherin and associated protein in cancer invasion and metastasis.1) The mechanism for reduction of E-cadherin expression. Among cultured cancer cell lines, no disorder was detected in E-cadherin gene. There was a cell line which dose not express E-cadherin protein in spite of the possession of its mRNA.This might suggest the post transcriptional regulation mechanism of E-cadherin protein.2) Degradation of E-cadherin by proteolysis. We revealed that a degraded form of E-cadherin was produced in cancer tissues, escaped into blood and, in consequence, detected at high level in the serum of cancer patients. Since more than 60% of gastric cancer patients showed high level of serum E-cadherin, its clinical application as a tumor maker is expected. The cancers with high serum E-cadherin had less amount of E-cadherin in cell surface. Thus, degradation by proteases might explain the reduction of E-cadherin in vivo.3) Regulation of E-cadherin function by beta-catenin. In cancer cell line and tissue, we detected reduction and/or tyrosin phosphorylation of beta-catenin, which resulted in decline of intercellular adhesion. Tyrosin phosphorylation of b-catenin was induced by EGF.4) Regulation of tight junction formation by E-cadherin. Occludin, a major tight junction protein, was directly associated with ductal formation. Since E-cadherin was indispensable for the expression of occludin, E-cadherin plays as important role in the regulation of differentiation through occludin expression.5) beta-catenin in the signal transduction of APC.beta-Catenin in cytosol, which is not bound to E-cadherin, was increased in cancerous tissues. It is interesting that cytosolic beta-Catenin was accumulated not only in colorectal cancers but also in esophageal cancers, where the mutation of APC was seldom observed.