神经细胞粘附分子调控黑色素瘤进展的分子机制及其作为靶向分子的潜在应用研究

The neural cell adhesion molecule (NCAM) was recently shown to be involved in the progression of various tumors with diverse effects.NCAM-specific antibodies have been used in molecular targeted therapy against tumors in a series of clinical trials.However,it is hardly known on the relationship between NCAM and melanoma. We previouly demonstrated for the first time that NCAM potentiates the cellular proliferation,invasion and metastasis of melanoma in vitro as well as in vivo and found out that β-catenin plays an important role in the proliferation of melanoma evoked by NCAM. It was also shown that NCAM promotes the proliferation of B16F0 melanoma cells by activation of β-catenin signaling through fibroblast growth receptor (FGFR) rather than the canonical Wnt pathway. Furthermore, NCAM could interact with FGFR, β-catenin, and glycogen synthase kinase-3β(GSK-3β).The present study is intended to investigate the roles of NCAM in the human derived melanoma cells.Firstly, based upon analysis of clinical histological samples,we will intend to elucidate the relaionship between NCAM and the progression of melanoma.Secondly,it will be investigated whether NCAM knockdown could suppress the proliferation and invasion of human derived melanoma cell lines in vitro. The findings of the present study will reveal a novel regulatory role of NCAM in the progression of melanoma that might serve as a new therapeutic target for the treatment of melanoma.

临床报道神经细胞粘附分子（neural cell adhesion molecule, NCAM）和黑色素瘤进展有关联，我们的前期工作首次揭示了NCAM能够显著促进小鼠黑色素瘤的生长和转移，并通过NCAM/FGFR/GSK-3β/β-catenin蛋白复合体调控β-catenin以控制增殖。本课题拟通过临床病理分析试图初步阐述NCAM和人类黑色素瘤进展之间的关系；同时，拟通过RNA干扰和高表达NCAM的方法，考察NCAM对人类不同发展阶段的黑色素瘤生长和转移的调控。本课题的研究成果将有助于阐明NCAM在黑色素瘤进展中所起的作用和分子机制，也为黑色素瘤新的治疗靶点的发现提供重要依据。

多项研究表明，神经细胞粘附分子（neural cell adhesion molecule，NCAM)和多种癌症的进展相关联，但是关于NCAM和黑色素瘤的关系研究很少。我们曾首次报道过，小鼠的黑色素瘤细胞高表达NCAM，而且NCAM可以促进小鼠黑色素瘤细胞的增殖和转移。在分子机制上，我们第一次发现了NCAM通过FGFR/GSK-3β/β-catenin信号调节细胞增殖。但是NCAM和人类黑色素瘤的相关关系目前仍然未知。本研究发现，NCAM在人类黑色素瘤组织内呈现高表达，其表达水平显著性高于黑痣和正常的皮肤，同时NCAM的表达水平和黑色素瘤的进展似乎呈现相关性。另外，通过体外多种黑色素瘤细胞系实验，我们发现NCAM可以促进人类黑色素瘤细胞的增殖和侵袭，而在调控的分子机制上，本研究初步确定了β-catenin可能是NCAM调控黑色素瘤细胞增殖的中介分子，同时合并有PI3K/Akt通路和MAPK通路的参与。我们的工作为进一步研究NCAM促进人类黑色素瘤进展的分子机制以及其作为潜在的靶向分子奠定了一个良好的基础。