Girdin与PI3K/Akt信号通路在调控胰腺癌血管生成中的相互作用机制研究

Pancreatic cancer is a difficult early diagnosis, malignant degree and very high malignant of digestive tumor, the reasons for the high mortality rate is mainly found in the late and early metastasis. Girdin is a new kind of actin binding protein, is a molecule consisting of 1870 amino acid residues of the protein,also named as Akt phosphorylation enhancer, and is closely related to cell migration.Girdin will be significantly increased expression in neonatal nerve cells and tumor cells, and is also closely related to angiogenesis . Advance experiment found that high expression of Girdin in pancreatic cancer is closely related to the occurrence and development , suggesting that Girdin involved in pancreatic cancer. Because Giridn protein can activate the PIK3/Akt signal pathway, while the activity of PI3K/Akt signaling pathway in pancreatic cancer, suggesting that Girdin may occur the development process through PI3K/Akt signaling pathway in pancreatic cancer. We intend to pancreatic cancer cell PANC-1 as the research object, the establishment of animal model of pancreatic cancer in nude mice, using Girdin transgenic technology, detecting changes of PI3 / Akt signaling pathway, detection the mechanism on angiogenesis.

胰腺癌是一种早期诊断困难恶性程度很高的消化道恶性肿瘤，死亡率高的原因主要是发现时已处于中晚期及早期转移。Girdin是一种新的肌动蛋白结合蛋白，是一个由1870个氨基酸残基构成的大分子蛋白质,又被命名为 Akt 磷酸化增强子,与细胞的迁徙运动密切相关。在新生神经细胞和肿瘤细胞内Girdin表达量会明显升高，与新生血管生成也密切相关。前期预实验发现Girdin的高表达与胰腺癌的进展密切相关，提示Girdin基因参与胰腺癌的发生发展。由于Giridn蛋白可激活PIK3/Akt信号传导系统，而PI3K/Akt信号通路的活性化参与胰腺癌的发生，提示Girdin可能通过PI3/AKt信号通路调控胰腺癌的发生发展过程。本课题拟以PANC-1胰腺癌细胞为研究对象，建立裸鼠胰腺癌动物模型，利用Girdin转基因技术，检测PI3K／Akt信号通路的变化，检测其对新生血管生成的影响及作用机制。

本课题在此三年中对Girdin在胰腺癌中的作用机制展开深入研究。我们针对几种常见胰腺癌细胞进行筛选，选出PANC-1作为研究靶点细胞，通过逆转录病毒的敲除，验证了Girdin促进了胰腺癌细胞的侵袭及转移；在裸鼠成瘤实验中，Giridn敲除后，肿瘤生长明显减慢。其后，本课题组，通过PANC-1胰腺癌细胞针对磷酸化/乙酰化组学，寻求在胰腺癌中位于下游受Girdin蛋白调控的同时发生两种修饰的蛋白种类，挑选出共修饰（overlap）和上下调最明显的5种蛋白（XPO1、VCL、CTTN、CRTC2、PPP1R14A）。在其中我们筛选出了Cortactin（基因CTTN）做为切入点；此位点目前尚未被报道。试验表明了Girdin 敲除后, Cortactin（基因CTTN）的K161ac位点在下调了0.663倍；CortactinS47ph位点下调了0.666倍。综上所述，我们验证了Girdin促进了肿瘤的增值、侵袭及转移，在其传导信号通路中，发现新的下游分子Cortactin，具有重要的临床研究价值。我们期待以Girdin为靶点，进行基因干预，会大大提高胰腺癌病人的生存质量及生存期。