负性共刺激分子B7-H3与c-Met结合调控EMT促进结直肠癌的转移及机制

Colorectal cancer is a serious threat to human health. And metastasis is the key factor of poor prognosis. Recently, we have found that the negative costimulation molecule B7-H3 are highly expressed in colorectal cancer tissues and their expression levels correlated with severity of this cancer. The abnormal expression of B7-H3 in colorectal cancer foci is closely related to tumor metastasis. We have further discovered that B7-H3 regulates the epithelial-mesenchymal transition (EMT), migration and invision of colorectal cancer cells. In particular, we have confirmed that B7-H3 can combine with tumor protein c-Met, which can regulate the EMT to promote tumor metastasis by Akt signaling pathways. But the mechanism between B7-H3 and tumor metastasis is not yet clear. To further investigate the molecular mechanisms, we will clarify the relationship of B7-H3 and EMT in clinical colorectal cancer tissues and cells. We will further confirm the B7-H3 and E-cadherin expression in fresh tumor tissue. Next, we will verify that B7-H3 binds to c-Met by IP and Western Blot and regulates the EMT of colorectal cancer cells via in vitro and in vivo analysis. At last, we put forward the plan of therapy by B7-H3/c-Met/Akt signal interference antibody. In general, the achievement of this program will improve the regulation mechanism research of EMT and provide the new target for clinical tumor immunotherapy.

结直肠癌是严重威胁人类健康的重大疾病，转移是导致结直肠癌预后不良的关键因素。我们前期研究发现：负性共刺激分子B7-H3在结直肠癌中异常高表达，随着癌变过程的进展其表达水平也逐步上调，并与结直肠癌患者肿瘤转移的发生密切相关；进而研究发现B7-H3可与原癌基因编码蛋白c-Met结合，通过Akt信号通路调控结直肠癌细胞的上皮间质转化（EMT）促进肿瘤的迁移、侵袭和转移，但确切的机制尚待研究。本项目以此为切入点在临床标本及结直肠癌细胞系中进一步分析B7-H3与EMT的相关性及临床意义，并利用肠癌组织临床标本、细胞株及模型动物进行体内外实验论证B7-H3对EMT的调控作用及分子机制，最后验证B7-H3/c-Met/Akt信号干预对结直肠癌转移的治疗效果。本项目所获研究结果将深化对结直肠癌EMT进程调控机制的认识，为临床早期治疗结直肠癌并预防其转移提供新的分子靶点。

结直肠癌是严重威胁人类健康的重大疾病，转移是导致结直肠癌预后不良的关键因素。我们前期研究发现：负性共刺激分子B7-H3在结直肠癌中异常高表达，且调控结直肠癌细胞的上皮间质转化（EMT）促进肿瘤的迁移、侵袭和转移，但确切的机制尚待研究。鉴此，本项目以人结直肠癌为研究对象，B7-H3和c-Met相互作用为主线，通过临床标本和体内外实验多个层面的研究，进一步探讨B7-H3调控结直肠癌EMT促进转移的作用机制及临床意义。我们通过临床标本分析和体内外实验证实共刺激分子B7-H3与结直肠癌临床病理和进展密切相关，继而发现B7-H3通过EMT机制加速结直肠癌细胞发生间质化转变，进而促进肿瘤的进展与转移，B7-H3分子有望成为监测结直肠癌转移的有价值的生物标志。更为重要的是本项目首次发现结直肠癌细胞表达B7-H3可以与原癌基因编码蛋白c-Met相关作用，促进c-Met信号及相应生物学功能，进而阐明了B7-H3调控结直肠癌EMT进程促进肿瘤进展与转移的作用机制，为结直肠癌转移的免疫干预提供一个新的靶点。