结直肠癌（CRC）转移是病人最主要的死因。我们前期证实发现CNPY2亚型2（CNPY2-2）是一种新型分泌蛋白、可能促进新生血管形成。最近我们在CRC研究的预实验中发现：CNPY2-2在CRC患者肿瘤组织及外周血中高表达、且与不良预后显著正相关；进一步细胞芯片结果提示CNPY2-2表达与上皮间质转化(EMT)相关。本项目将承前启后，拟在一系列体内外实验中、结合临床检测与分析：1）明确CNPY2-2依赖HIF-1α表达水平的调控机制；2）研究并解析CNPY2-2促CRC血管生成和通过抑制p53通路启动EMT的分子机制；3）在CRC裸鼠肝转移模型中，观察并确证CNPY2-2可促进CRC侵袭转移。深入阐明HIF-1α上调CNPY2-2促血管生成并启动EMT促进CRC侵袭转移的确切分子机制，为揭示CRC转移机理和寻找抗肿瘤治疗新靶点提供实验研究基础和新线索。

Metastasis is the main cause of patient death in patients with colorectal carcinoma (CRC). Our recent studies have demonstrated that Canopy2 isoform 1(CNPY2-1) was a secreted angiogenic growth factor. We newly found that Canopy2 isoform 2（CNPY2-2）was a novel secreted protein that significantly induced angiogenesis. CNPY2-2 frequently overexpressed in CRC tissue and peripheral serum, which was positively correlated with the poor prognosis. The Gene Expression Microarray results indicated that CNPY2-2 was associated with epithelial-mesenchymal transition（EMT）. Follow the above project, a series of in vivo and in vitro experiments will be used to further investigate the following issues by combining with CRC clinical samples: 1) to indentify effects of HIF-1a on improving CNPY2-2 expression in CRC cell lines and its associated molecular signaling pathway and mechanisms; 2) to elucidate the molecular mechanisms of CNPY2-2 in promoting CRC cells angiogenesis, EMT, invasion and metastasis through down-regulating p53 pathway; 3) finally, to verify that CNPY2-2 can promote CRC cell invasion and metastasis and find out the relative targets by animal model. The effect of HIF-1a in up-regulating CNPY2-2 expression to promote angiogenesis, invasion and metastasis, as well as its specific molecular mechanisms will be discoved. Our study may provide better experimental basis and novel clues for further revealing the molecular mechanisms of CRC metastasis and potential new targets of anti-cancer treatment.