淋巴转移(LM)显著影响胃癌预后。大样本临床研究证实胸苷磷酸化酶(TP)与胃癌LM密切相关，但其促LM的机制不明。SIX1是促LM的重要转录因子。我们前期发现TP与人胃癌LM程度、肿瘤淋巴管密度及SIX1表达正相关，同时高表达TP与SIX1的患者生存时间进一步缩短。故我们推测TP与SIX1可能协同促进胃癌LM并影响其预后。目前我们已发现TP过表达质粒转染胃癌细胞后SIX1表达增加；TP可激活SMAD的上游通路之一PI3K-AKT；SMAD与SIX1共同调控VEGF-C，促进淋巴管新生与转移；经预测SIX1可与TP启动子区结合。本项目拟验证TP-SIX1共表达与胃癌预后的相关性，探索TP是否通过PI3K-AKT-SMAD通路激活SIX1，SIX1是否刺激TP过表达，并初步探讨靶向TP-SIX1正反馈环在抑制胃癌LM中发挥的作用。本研究有助于阐明胃癌LM的新机制，为抗胃癌转移新药研发提供线索。

Lymphnodes metastasis is an independent prognostic factor of gastric cancer(GC). Thymidine phosphorylase (TP) is significantly associated with lymph nodes metastasis in GC, however, the molecular mechanisms underlying TP and lymphatic metastasis are largely unknown. SIX1, a homeodomain-containing transcription factor, is involved in lymphangiogenesis and lymphatic metastasis. Our previous study observed significant associations among TP, VEGF-C/SIX1 expression and lymphatic metastasis of GC. GC patients with co-expression of TP and SIX1 had much poor survival. Hence, we speculate that TP and SIX1 might synergistically improve lymph node metastasis of GC. We have found that overexpression of TP increased SIX1 expression in gastric cancer cells, TP activated PI3K-AKT which located in the upstream pathway of SMAD; then SMAD combined with SIX1, co-regulate the expression of VEGF-C, thereby promoting lymphangiogenesis and metastasis. SIX1 can binds to the promoter region of TP. Thus, we postulate that TP might activate SIX1 through PI3K-AKT-SMAD pathway and in turn, SIX1 stimulates TP expression. We intend to investigate and verify the effect of TP-SIX1 positive feedback loop on the lymphatic metastasis of GC. This study may help to elucidate the mechanism underlying lymphatic metastasis in GC and is expected to provide us with novel ideas for design of anti-tumor metastasis drugs.