SCG2通过激活HIF-1α蛋白泛素降解途径抑制结直肠癌肿瘤血管生成的分子机理研究

肿瘤远处转移是制约结直肠癌疗效的瓶颈问题，目前缺乏有效防治措施，关键在于相关机制研究不清楚。我们前期通过临床样本研究发现颗粒蛋白SCG2在结直肠癌组织中低表达，且癌组织中SCG2表达水平与肿瘤病程负相关，同时癌组织中SCG2低表达水平与患者不良预后密切相关；进一步通过预实验发现过表达SCG2可显著抑制结直肠癌肿瘤血管生成。基于文献分析和预实验结果，我们提出了过表达SCG2可能在抑制结直肠癌转移进程中有着重要作用，它可能通过泛素降解HIF-1α抑制VEGF表达进而抑制肿瘤血管生成的假说。因此，本项目拟采用结直肠癌动物和细胞模型，通过Co-IP实验、泛素降解实验、HUVEC成管实验和侵袭实验等研究SCG2通过调控HIF-1α表达调控结直肠癌肿瘤转移的作用，并深入研究SCG2调控HIF-1α泛素降解的机制。本研究将为结直肠癌转移机制研究提供潜在的方向，并探究潜在的转移防治策略。

Distant metastasis is a critical prognostic factor, and there is lack of effective prevention and treatment measures due to the unclear mechanism. In our previous study, we found that the SCG2, a granule protein, was significantly downregulated in malignant colorectal cancer tissues. The expression of SCG2 in colorectal cancer tissues was negatively correlated with the progression of disease and downregulation of SCG2 in colorectal cancer tissues is correlated with poor prognosis of colorectal cancer patients. Furtherly, we found that ectopic SCG2 expression of colorectal cancer cells significantly inhibited tumor angiogenesis in pre-experimentation. Based on the literature analysis and the results of the pre-experiment, we propose the hypothesis that ectopic SCG2 expression may play an important role in the inhibition of colorectal cancer metastasis, and it may inhibit VEGF expression leading to the inhibition of tumor angiogenesis through ubiquitous degradation of HIF-1α. Therefore, we want to investigate the role of SCG2 in regulating colorectal cancer tumor metastasis by regulating HIF-1α through Co-IP assay, ubiquitin degradation assay, HUVEC tube formation assay and invasion assay using animal and cellular models of colorectal cancer, and also investigate the mechanism of SCG2 regulating HIF-1α ubiquitination degradation in depth in this study. It could provide a potential directions for the study of metastasis mechanism of colorectal cancer and explore a potential prevention and control strategy for distant metastasis.