STAT1蛋白调控新型溶瘤病毒VG161在胰腺星状细胞中复制的作用及机制研究

胰腺星状细胞（PSC）在胰腺癌中形成“物理屏障”以阻碍药物渗透及免疫细胞浸润。本课题组通过体内、外实验首次发现活化的PSC细胞可切断新型HSV-1型溶瘤病毒VG161在胰腺癌中的传播，从而造成病毒的失效。进一步探索原因，发现VG161在活化PSC细胞中无法有效复制，而STAT1蛋白是其中关键。结合前期研究，我们推测STAT1蛋白通过JAK-STAT通路调控经典抗病毒蛋白PKR的转录翻译，进而促进eIF-2α磷酸化。而高浓度磷酸化eIF-2α抑制了细胞内蛋白合成，最终导致VG161无法在活化PSC中有效复制。本课题拟在前期研究的基础上，结合免疫共沉淀、GST-pulldown、质谱分析等方法进一步验证和阐明STAT1在活化PSC中影响VG161复制的作用及相关机制。以STAT1及相关通路为靶点，以期攻破上文所述“物理屏障”，为溶瘤病毒疗法在胰腺癌上的应用提供新的思路。

Pancreatic stellate cell (PSC) can form “physical barrier” in pancreatic cancer to prevent drug penetration and immune cell infiltration. Through experiments in vivo and in vitro, for the first time, our team discovered that activated PSC cells could disturb the transmission of novel HSV-1 oncolytic virus, VG161, in pancreatic cancer, thus resulting in impotent virus. After further exploration, it was found that VG161 could not replicate effectively in activated PSC cells due to STAT-1 protein, which was the key factor. Combined with previous studies, we suspect that STAT1 regulates the translation of PKR through JAK-STAT pathway, and then promotes the phosphorylation of eIF-2α. However, high concentration of phosphorylated eIF-2α inhibited the synthesis of intracellular proteins, which ultimately resulted in the failure replication of VG161 in activated PSC. On the basis of previous studies, our study combined methods of co-immunoprecipitation, GST-pulldown, mass spectrometry et al. to further demonstrate and elucidate the effect and related mechanism of STAT1 affecting VG161 replication in activated PSC. Targeting on STAT1 and its related pathways, we hope to break this “physical barrier” and provide a new idea for the application of oncolytic virus therapy in pancreatic cancer.