血管生成是肿瘤生长转移过程中的最重要环节之一，但是肿瘤血管生成的调控机制仍未完全揭示。我们前期研究发现跨膜丝氨酸蛋白酶4 (TMPRSS4)不仅可通过激活ERK1/2通路诱导肝癌上皮间质转化，还显著促进肝癌血管生成，但是ERK1/2抑制剂并不能抑制TMPRSS4诱导的肝癌血管生成。我们通过基因芯片对比发现TMPRSS4高表达肝癌TSC1基因的表达显著受到抑制而NF-κB被活化。鉴于TSC1/mTOR信号通路与血管生成密切相关，我们推测TMPRSS4有可能是通过激活IKK/NF-κB使TSC1失活，引起TSC2的泛素化和降解，进而促进RHEB基因活化从而激活肝癌mTOR信号通路和肿瘤血管生成。本项目欲进一步证实上述假说，明确TMPRSS4在肝癌血管生成中的作用机制，以完善我们对肿瘤血管生成调控机制的理解，为抗肝癌血管生成提供新的治疗靶点，提高肝癌患者的预后。

Angiogenesis is one of the most important events in tumor growth and metastasis, but the mechanism regulating tumor angiogenesis is not fully clarified. Our previous studies found that TMPRSS4 not only induced epithelial-mesenchymal transition of hepatocellular carcinoma (HCC) through activating ERK1/2 pathway, but also markedly promoted the angiogenesis. However, ERK1/2 inhibitor could not suppress TMPRSS4 induced angiogenesis of HCC. Microarray comparison revealed that TSC1 gene expression was significantly inhibited while NF-κB was activated in TMPRSS-overexpressing HCC. Because of the close correlation of TSC1/mTOR signaling pathway with angiogenesis, we speculate that TMPRSS4 may inactivate TSC1 through activating IKK/NF-κB, thereby cause the ubiquitination and degradation of TSC2, which in turn activates RHEB and mTOR signaling pathway and promote angiogenesis. In this study, we want to confirm this hypothesis, clarify the mechanism of TMPRSS4 in regulating angiogenesis of HCC, improve the understanding of tumor angiogenesis, and provide a new target for anti-angiogenesis treatment HCC.