恶性肿瘤早期淋巴道转移发生机制不清，一直是肿瘤学研究难题。原癌基因表达产物接头蛋白Crk参与整合蛋白等分子信号转导，正成为肿瘤转移恶化研究的热点分子，但其与肿瘤淋巴道转移的关系尚未涉及。本组前期工作发现1)Crk及其下游分子Rack1在高淋巴道转移力鼠肝癌细胞株Hca-F中表达均明显上调，且CRKI上调与肺鳞癌发展和胃癌淋巴道转移呈正相关；2)抑制整合蛋白信号强度能降低肝癌荷瘤鼠的肿瘤转移和死亡率，明显降低Hca-F迁移侵袭能力。本项目拟1)通过调控Crk在肝癌高低淋巴道转移力Hca-F和Hca-P细胞中的蛋白表达水平，考察该变化对肿瘤细胞体内外黏附、侵袭、迁移及淋巴道转移潜能的影响；2)研究整合蛋白/Crk信号转导通路中关键蛋白分子及CrkII/CrkL自抑制磷酸化水平的相互关系，明确其分子调控机制；3)探讨CRK作为临床肿瘤转移预警潜在靶标的可行性，为恶性肿瘤诊治提供新的可行性途径。

The mechanism of early lymphatic metastasis for malignant tumors is unclear, which is still the leading problem for oncology. As the expression product of proto-oncogene, the adaptor protein Crk is involved in signal transduction pathways such as integrin signaling transduction. The Crk family proteins are becoming hotspot molecules for tumor metastasis and maligancy, however, the association of Crk with tumor lymphatic metastasis has not been touched. Previous study from our group indicated that 1) Crk and its down-stream signal molecule Rack1 were both up-regulated signifcantly in mouse hepatocarcinoma cell (Hca-F) with high lymphatic metastatic potential. The up-regulation of CRKI was found to be positively correlated with the development of lung squamous cell carcinoma and lymphatic metastasis of gastric cancer; 2)The suppression of integrin siganl could decrease tumor metastasis and mortality rate of mice with hepatocarcinoma and could significantly decrease the mobility ability of Hca-F. This proposal aims to 1) regulate the expression levels of Crk family members in tumor cells with high (Hca-F) and low (Hca-P) lymphatic metastasis potentials and to investigate the corresponding changes on the capacities of tumor cell adhesion, invasion, motility and metastasis in vitro and/or in vivo; 2) to unreveal the associations and regulation mechanism among the critical proteins and autoinhibitory phosphorylation of CrkII/CrkL involved in the integrin-Crk signal transduction pathway; 3) to investigate the possibibity of CRK utilized as potential predictive markers for clinical tumor metastasis and provide a new feasible approach to the diagnosis and treatment of malignant tumors.