Essential role of Cadherin family in esophageal cancer and Potential for a novel molecule of targeted therapy

本研究的目的是分析钙粘蛋白家族在食管癌发生中的作用，阐明N-钙粘蛋白与肿瘤微环境的关系。此外，通过抑制N-cad的作用，一种新的分子靶向治疗被视为一种全新的方法。首先，我们证实3/10例Barrett‘s癌组织中N-cad表达，尤其是在肿瘤侵袭前沿强表达。在食道癌细胞系中，TE4和10表达N-cad。I型胶原和转化生长因子对这些细胞的刺激导致N-cad的过度表达，而原本不表达N-cad的细胞则没有变化。然而，受刺激的细胞出现了形态变化，表明可能已经诱导了EMT。我们还在前人报道的基础上，通过钙粘附素研究了铁调控与EMT的关系。我们证实了该化合物在体内和体外的抗肿瘤作用。体内采用缺铁饮食，体外采用铁络合剂。在缺铁条件下，N-cad在体外的表达降低，细胞的迁移和侵袭能力降低，提示N-cad可能是肿瘤侵袭和生长的重要分子。现在我们使用siRNA-N-cad和降低癌细胞中的表达，并将证实同样的现象在食道癌细胞中。作为未来，我们计划考虑使用N-cad抑制剂的新的多学科癌症治疗。

In this research, our purpose is the analysis of cadherin family in esophageal carcinogenesis and to clarify the relation of N-cadherin and tumor microenvironment. In addition, a new molecular target therapy was aimed as a completely new approach by inhibiting the action of N-cad. First, we confirmed that 3/10 cases in Barrett's cancer expressed N-cad, especially strong expression in leading edge of tumor invasion. In esophageal cancer cell lines, TE4 and 10 expressed N-cad. Stimulation of collagen I, and TGF on those cells lead to over-express N-cad, in the other side, no change in cells which originally not expressed N-cad. However, stimulated cells showed morphological changes, suggesting EMT may have been induced. We also investigated relation of iron control and EMT through cadherins, based on the previous reports. We confirmed the antitumor effect of that in vivo and vitro. In vivo, we used iron deficient diet and, in vitro used iron chelator. In iron deficient conditions, N-cad expression was decreased in vitro, and the cells showed decreased those migration and invasion ability, suggesting that the possibility that N-cad is an important molecule in cancer invasion and tumor growth. Now we used siRNA-N-cad and reduced expression in cancer cells and would confirm the same phenomenon in esophageal cancer cells. As the future, we scheduled to consider a new multidisciplinary cancer therapy using N-cad inhibitors.