SEMA6D在结直肠癌发生发展中的功能和机制研究

Colorectal cancer (CRC) is one of the major causes of cancer-related deaths in the world, and the incidence and mortality of CRC have increased rapidly in China in recent years. Uncontrolled growth and distant metastasis are hallmarks of CRC, but the mechanisms are poorly understood. It is very important to study the molecular mechanism of metastasis of colorectal cancer to explore the novel bio-markers for the precise diagnosis and individualized medication. Nearly 20 semaphorin genes were found in mammals and their protein products were found to be involved in cell migration, immune response, angiogenesis, and tumor progression. SEMA6D has been demonstrated to play great roles in malignant pleural mesothelioma, breast cancer and gastric cancer,especially the roles of oncogene.By bioinformatics analysis, it was found that the expression of SEMA6D in CRC tissues and cells was lower than that in normal tissues and cells. Meanwhile, the expression of SEMA6D was correlated with the prognosis in different cancers. Overexpression of SEMA6D could inhibit the proliferation and metastasis of CRC cells. There were two CpG islands in the promoter of SEMA6D. The CpG islands may be methylated because of downregulation of SEMA6D in CRC. It means that SEMA6D may play roles just as tumor suppressor but not oncogene in CRC. In this project, we will validate the relationship between expression of Sema6D and prognosis of patients by expanding the number of samples. The effects of SEMA6D on proliferation and metastasis of CRC were studied in vitro and in vivo. Meanwhile, the dysregulation of SEMA66D and mechanisms of above function of SEMA6D were explored by experiments. Thus will provide a possible molecular biomarker for the diagnosis and treatment effect prediction, as well as personalized treatment of colorectal cancer as a scientific experimental evidence.

结直肠癌（Colorectal cancer,CRC）是目前世界上癌症相关主要死亡因素之一，转移后预后较差。深入研究CRC发生发展中的关键分子机制对于其早期诊断及治疗具有重要意义。轴突导向分子semaphorin家族被证实在肿瘤中发挥重要作用，但其在结直肠癌中的作用却鲜有报道。申请人通过生物信息学分析发现SEMA6D在CRC组织表达明显下调，与多种肿瘤的预后相关；初步试验发现SEMA6D在结直肠癌组织和细胞中的表达低于正常组织和细胞；过表达SEMA6D可以抑制肠癌细胞的增殖和迁移；在SEMA6D的启动子区存在两个较大的CpG岛，结合表达下调，提示可能存在甲基化。上述结果提示SEMA6D在结直肠癌的发生和发展中可能发挥抑癌基因作用。本研究拟扩大样本分析SEMA6D表达与预后的关系，深入探索SEMA6D在CRC中的功能及作用机制，为CRC的诊断，疗效测定，治疗提供可能的分子标志物和治疗靶点。