活血化瘀中药调控缺氧微环境HIF-1α/WSB1/NF-κB信号通路对大肠癌血管新生的作用机制研究

血管新生是影响肿瘤的发生、发展和转移的重要因素，控制血管形成是抑制肿瘤生长和治疗肿瘤的重要途径。课题组前期发现，HIF-1α介导的缺氧微环境是大肠癌血管新生的直接原因，活血化瘀中药通过下调VEGF表达可以抑制大肠癌血管新生。.我们研究证实HIF-1α能够能解离HIPK2/WSB1复合物，释放WSB1。活血化瘀中药通过抑制HIF-1α，上调HIPK2，改善缺氧微环境。申请人还发现HIPK2与NF-κB磷酸化水平呈负相关。因此，我们推测HIPK2可能是调控HIF-1α/WSB1/NF-κB信号通路介导的大肠癌血管新生的重要途径之一。本研究采用CRISPR/Cas9、荧光免疫染色、肠道特异性基因敲除小鼠模型等技术，研究活血化瘀中药对HIF-1α/WSB1/NF-κB信号通路的调控作用，这对于明确中药抗大肠癌血管新生作用机制，探索中医药防治肿瘤的新途径，具有重要的意义。

Angiogenesis is an important factor in the occurrence, development and metastasis of tumor. Controlling angiogenesis play an important role in inhibiing tumor growth and treatment. Our previous studies showed that HIF-1α mediated hypoxic microenvironment is a direct cause of colorectal cancer angiogenesis. TCM for activating blood circulation can inhibit angiogenesis via VEGF expression in colorectal cancer..Our study confirmed that HIF-1α can be able to dissociate HIPK2/WSB1 complexes release WSB1. TCM for activating blood circulation can inhibit HIF-1α, increase HIPK2, improve hypoxia microenvironment. We also found that HIPK2 negatively correlated with phosphorylation of NF-κB. So, we speculate the mechanism of angiogenesis aroused by that HIPK2 via activating HIF-1α/WSB1/NF-κB signaling pathway in colorectal cancer. In this study, we explore the effect of TCM for activating blood circulation in HIF-1α/WSB1/NF-κB signaling mediated angiogenesis in colorectal cancer, through gut-specific gene knockout mouse model model, CRISPR/Cas9, immunofluorescence staining, and other experimental technology. This study of ours will not only elucidate the therapeutical mechanism of traditional chinese medicine that activating blood and dissolving stasis , but also define novel treatable targets for TCM in colorectal cancer angiogenesis.