C型凝集素样受体2在胃癌发生、迁移及失巢凋亡中的作用

Gastric cancer is one of the most common malignancies in China with high incidence rate and short survival period. Tumor invasion and lymphatic metastasis is related with the prognosis of gastric cancer and the recurrence. CLEC-2 is a C-type lectin mainly expressed on the surface of platelet, dendritic cells and neutrophils. Podoplanin, one of the endogenous ligands of CLEC-2, is the marker of lymphatic vessel endothelial cell, and is capable to activate the downstream signal of CLEC-2 by interacting with the C-type lectin domain in the extracellular part of CLEC-2. We found the expression of CLEC-2 in all gastric cell lines on both mRNA and protein levels, and identified its expression difference between gastric cancer and adjacent normal gastric mucosa by immunohistochemistry. To determine the biological significance of the specific expression of CLEC-2, we carry out this study to check whether CLEC-2 in gastric cancer is related with the migration, invasion or anoikois, and how the signal conducting of CLEC-2 works here.

胃癌是国内最常见的恶性肿瘤之一，其发生率高，生存期短。肿瘤侵袭和淋巴转移是影响胃癌预后的重要因素，也是胃癌复发的危险因子。CLEC-2是一种新型的C型凝集素样受体，主要表达在血小板，树突状细胞和中性粒细胞。而淋巴管内皮细胞标志分子podoplanin是CLEC-2的内源性配体，通过结合到CLEC-2细胞外C型凝集素样结构域从而活化CLEC-2的下游信号传导。我们前期研究发现CLEC-2在胃癌细胞系上的mRNA和蛋白水平都有表达，并通过免疫组化证明在胃癌组织和癌旁组织上的表达存在差异。为了进一步确定CLEC-2在胃癌细胞中表达的生物学意义，本课题拟对CLEC-2在胃癌细胞上的表达是否影响胃癌的迁移、侵袭和失巢凋亡等肿瘤行为以及作用的信号机制进行研究。

C型凝集素样受体2（CLEC-2）是dectin-1基因簇中在正常胃组织中表达最高的C型凝集素样受体，本课题通过分析胃癌组织芯片中该蛋白的表达水平，结合细胞和动物实验，对CLEC-2参与调控胃癌转移的分子机制进行了初步研究。我们发现CLEC-2在胃癌患者中普遍表达降低。CLEC-2的活化可以抑制胃癌细胞株的转移和侵袭，而CLEC-2下调以后会促进胃癌的转移和侵袭，而且这一过程是通过Syk信号通路调控的。CLEC-2与syk在胃癌细胞中的互作和调控，不仅影响了CLEC-2的稳定性，还能够影响AKT的磷酸化以及下游GSK-3beta、PI3K、Snail、以及E-cad等蛋白的表达。综合上述结果，本研究为探讨CLEC-2调节胃癌转移的机制奠定了坚实的工作基础，并为胃癌诊断和治疗预后提供了潜在的靶点。