Rosivatz Erika, Becker Ingrid, Specht Katja, Fricke Elena, Luber Birgit, Busch Raymonde, Höfler Heinz, Becker Karl-Friedrich
Klinikum rechts der Isar, Institut für Pathologie, Technische Universität München, Germany.
Am J Pathol. 2002 Nov;161(5):1881-91. doi: 10.1016/S0002-9440(10)64464-1.
Epithelial-mesenchymal transition (EMT) involving down-regulation of E-cadherin is thought to play a fundamental role during early steps of invasion and metastasis of carcinoma cells. The aim of our study was to elucidate the role of EMT regulators Snail, SIP1 (both are direct repressors of E-cadherin), and Twist (an activator of N-cadherin during Drosophila embryogenesis), in primary human gastric cancers. Expression of Snail, SIP1, and Twist was analyzed in 48 gastric carcinomas by real-time quantitative RT-PCR in paraffin-embedded and formalin-fixed tissues. The changes of expression levels of these genes in malignant tissues compared to matched non-tumorous tissues were correlated with the expression of E- and N-cadherin. From 28 diffuse-type gastric carcinomas analyzed reduced E-cadherin expression was detected in 11 (39%) cases compared to non-tumorous tissues. Up-regulated Snail could be found in 6 cases with reduced or negative E-cadherin expression. However, there was no correlation to increased SIP1 expression. Interestingly, we could detect abnormal expression of N-cadherin mRNA in 6 cases, which was correlated with Twist overexpression in 4 cases. From 20 intestinal-type gastric cancer samples reduced E-cadherin expression was found in 12 (60%) cases, which was correlated to up-regulation of SIP1, since 10 of these 12 cases showed elevated mRNA levels, whereas Snail, Twist, and N-cadherin were not up-regulated. We present the first study investigating the role of EMT regulators in human gastric cancer and provide evidence that an increase in Snail mRNA expression is associated with down-regulation of E-cadherin in diffuse-type gastric cancer. We detected abnormally positive or increased N-cadherin mRNA levels in the same tumors, probably due to overexpression of Twist. SIP1 overexpression could not be linked to down-regulated E-cadherin in diffuse-type tumors, but was found to be involved in the pathogenesis of intestinal-type gastric carcinoma. We conclude that EMT regulators play different roles in gastric carcinogenesis depending on the histological subtype.
上皮-间质转化（EMT）涉及E-钙黏蛋白的下调，被认为在癌细胞侵袭和转移的早期阶段起着重要作用。我们研究的目的是阐明EMT调节因子Snail、SIP1（两者均为E-钙黏蛋白的直接抑制因子）和Twist（果蝇胚胎发育过程中N-钙黏蛋白的激活因子）在原发性人类胃癌中的作用。通过实时定量逆转录聚合酶链反应（RT-PCR）对48例石蜡包埋和福尔马林固定的胃癌组织中Snail、SIP1和Twist的表达进行分析。将这些基因在恶性组织与配对的非肿瘤组织中的表达水平变化与E-钙黏蛋白和N-钙黏蛋白的表达相关联。在分析的28例弥漫型胃癌中，与非肿瘤组织相比，11例（39%）检测到E-钙黏蛋白表达降低。在6例E-钙黏蛋白表达降低或阴性的病例中发现Snail上调。然而，与SIP1表达增加无相关性。有趣的是，我们在6例中检测到N-钙黏蛋白mRNA异常表达，其中4例与Twist过表达相关。在20例肠型胃癌样本中，12例（60%）发现E-钙黏蛋白表达降低，这与SIP1上调相关，因为这12例中有10例mRNA水平升高，而Snail、Twist和N-钙黏蛋白未上调。我们首次研究了EMT调节因子在人类胃癌中的作用，并提供证据表明Snail mRNA表达增加与弥漫型胃癌中E-钙黏蛋白下调相关。我们在同一肿瘤中检测到N-钙黏蛋白mRNA水平异常阳性或升高，可能是由于Twist过表达。SIP1过表达在弥漫型肿瘤中与E-钙黏蛋白下调无关联，但发现其参与肠型胃癌的发病机制。我们得出结论，EMT调节因子在胃癌发生中根据组织学亚型发挥不同作用。
