慢性炎症参与了结直肠癌的发生、侵袭、转移。PSGL-1是白细胞重要的黏附分子，诱导下游信号通路产生炎症反应。在临床样本中我们发现结直肠癌组织中有PSGL-1阳性的白细胞浸润，其数量与肝转移呈负相关；其次，利用PSGL-1敲除的自发肠道腺瘤模型（APCMin/+小鼠），证实PSGL-1缺失导致小鼠肠道肿瘤数量增多，肿瘤体积增大，生存率显著下降，病理恶性程度加剧，提示PSGL-1缺失促进肿瘤的发展；通过炎症相关的蛋白芯片筛查到PSGL-1缺失后小鼠血液中CCL9和IGFBP6表达升高， 而肿瘤内的炎症信号信号TNF-α和p65/RelA上调。因此，假设PSGL-1缺失可能上调CCL9或IGFBP6来激活炎症通路促进了肿瘤的发展。本项目拟进一步采集大样本不同TNM临床分期标本，结合细胞、分子和动物实验，探究PSGL-1缺失促进肿瘤生长的分子机制；为临床有效治疗结直肠癌提供新的理论依据和药物靶点。

Chronic inflammation has been involved in the formation, development and even metastasis of colorectal cancer. P-selectin glycoprotein ligand 1(PSGL-1) is one of the important adhesion molecules on leukocytes and its deficiency will cause chronic inflammation. Now we found in the clinical specimens that PSGL-1 positive cells were largely accumulated in colorectal carcinoma and the number of PSGL-1 positive cells was negatively correlated with metastasis to the liver. Next, we crossed APCMin/+ mice carrying spontaneous colorectal neoplasm with PSGL-1 knock-out (PSGL-/-) mice, resulting in APCMin/+;PSGL-/- mice. Compared with APCMin/+ mice, APCMin/+;PSGL-/- mice had more the number of tumors and larger size, along with decreased survival rate and accelerated pathological process, suggesting that PSGL-1 deficiency promotes tumor development. Further studies showed that in APCMin/+;PSGL-/- mice, there was up-regulated expression of CCL9 (Chemokine (C-C motif) ligand 9) and IGFBP6 (insulin-like growth factor binding protein 6) in the peripheral blood and up-regulated expression of TNF-α and p65/RelA in the tumors. Hence we hypothesis that PSGL-1 deficiency activates the signaling pathway involved in inflammation through up-regulating CCL9 or IGFBP6, thus promoting tumor progress. In this proposal, we will collect and detect more clinical samples，combining with animal experiments and cellular assays as well as molecular technology to validate and explore the hypothesized mechanism.It should provide new theoretical and new drug target for colorectal cancer therapy.