剪接调控蛋白PTBP1调控mRNA选择性剪接、降解、翻译等过程。本课题组前期发现：PTBP1在肝癌表达上调，且与临床分期、肿瘤恶性程度、微血管密度、脉管侵犯、预后相关；敲低PTBP1抑制肝癌生长、侵袭、体外血管形成能力及肝癌细胞表达血管生成因子VEGF、TGFβ；敲低PTBP1下调NRP2 mRNA，改变VEGFR1剪接模式。因此，本项目拟通过一系列实验证实PTBP1是否通过调控VEGFR1选择性剪接和NRP2 mRNA稳定性从而调控VEGF/VEGFR、HGF/cMet等信号通路，进而调控肝癌细胞本身存活、侵袭、转移等，并通过这些通路影响肝癌细胞分泌sVEGFR1、VEGF、TGFβ等血管生成相关因子，进而影响血管内皮细胞的生物学行为，促进血管新生。这些研究对于阐述肝癌进展、血管生成新机制，识别鉴定肝癌进展新的相关标志物，鉴定新的抗血管治疗靶点等均具有十分重要的理论意义和潜在的应用价值。

Alternative splicing protein PTBP1 regulates the alternative splicing, decay and translation of mRNAs. Our recent data demonstrated that PTBP1 was significally overexpressed in hepatocellular carcinoma (HCC). Moreover, high PTBP1 level was associated with tumor clinical stage, tumor grader, micro vessel density (MVD), tumor cell vascular invasion and poor prognosis. Functional studies showed that knockdown of PTBP1supressed growth and invasion of HCC cells and inhibited tube formation of HUVEC cells in vitro. And knockdown of PTBP1 downregulated VEGF and TGFβ in HCC cells. We further revealed that knockdown of PTBP1 in HCC cells suppressed NRP2 mRNA expression and regulated VEGFR1 splicing. Based on these preliminary results, in the present project, we will determine whether PTBP1 regulates the VEGFR1 alternatively splicing and increases NRP2 mRNA stability, by which VEGF/VEGFR and HGF/c-Met signals are activated, and in turn promotes survival, invasiveness and metastasis of HCC cell itself. Then, we will investigate whether PTBP1 affects HCC paracrine of sVEGFR1, VEGF and TGFβ, which regulates the proliferation, apoptosis, migration, invasion and adhesion of endothelial cells and modulates tumor angiogenesis. In conclusion, these studies will provide a valuable theoretical basis for elucidating the new mechanisms of HCC progress and angiogenesis, identifying new markers of HCC progress and exploring new targets of anti-angiogenesis therapy in HCC.