TSC1/mTOR信号通路在TMPRSS4诱导肝癌血管生成中的作用研究

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.

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。

肝癌是典型的多血供肿瘤，血管生成在肝癌生长到转移过程中均起着重要作用。目前肝癌靶向药物主要通过抑制血管内皮生长因子 (VEGF)、血小板衍生生长因子(PDGF)和成纤维细胞生长因子(FGF) 这几种最常见的生长因子及其受体，来抑制肝癌的血管生成及生长转移，但是其临床客观缓解率仅为10-20%，病人生存获益也仅为几个月, 因此继续深入探索肝癌血管生成的调控机制十分重要。该研究首次发现肝素结合性表皮生长因子(HB-EGF)在肝癌血管生成中发挥重要的调控作用。跨膜丝氨酸蛋白酶4（TMPRSS4）不仅能促进HB-EGF前体的表达，还能通过激活EGFR/PI3K/AKT/mTOR信号通路促进MMP9对HB-EGF前体的酶解，将其转化为溶解型HB-EGF，进而发挥促进肝癌血管生成和侵袭转移的作用。而CRM197可通过抑制HB-EGF与EGFR结合而阻断这一过程，起到抑制肝癌新生血管的形成和肿瘤增殖的作用，并能增强肝癌对靶向药物索拉非尼的敏感性。研究还发现肝癌患者血清及肝癌组织HB-EGF水平均显著高于健康人群，HB-EGF 是肝癌微血管密度的预测指标，也是肝癌患者术后生存及复发的独立危险因素，