申请人最近研究发现，在鼻咽癌中抗氧化酶SOD2和Catalase失巢后表达上调，通过降低ROS抗鼻咽癌失巢凋亡。预实验表明在胃癌细胞失巢时以上抗氧化酶及SOD1、G6PD的表达并未上调，但线粒体烟酰胺核苷酸转氢酶（NNT）表达升高；同时在裸鼠腹腔胃癌结节中NNT也上调；敲低胃癌细胞NNT可升高ROS增加失巢凋亡。以上研究提示NNT可能通过抗氧化作用抑制胃癌细胞失巢凋亡。本项目设计如下内容：①建立胃癌失巢转移、NNT过表达/敲除细胞模型，进一步明确NNT在胃癌细胞失巢凋亡抵抗中的关键作用；②明确NNT是否通过增加NADPH，进一步激活GSH途径清除ROS抗失巢凋亡；③已知NNT催化NADH将[H]转移给NADP+生成NADPH，本项目拟明确为NNT提供H源的NADH的来源：葡萄糖和/或脂肪酸分解代谢？旨在阐明NNT的抗氧化作用在胃癌细胞失巢凋亡抵抗中作用及机制，为胃癌转移提供新靶点和新思路。

We have previously shown that up-regulated SOD2/Catalase promoted anoikis resistance via antioxidant ability. Recently, we have found the expression of antioxidant enzyme G6PD, SOD1/2 and catalase was not up-regulated， only found nicotinamide nucleotide transhydrogenase（NNT） was up-regulated in gastric cancer cells during suspension culture, also found NNT was high expression in intraperitoneal injection model; knockdown NNT enhance ROS and anoikis. Suggestting that NNT may induces anoikis resistance via antioxidant effect, however the mechanism was not certain.This project content designed as follows: ①To establish a mouse model for anoikis metastasis and NNT knock-out/ transgenic cell model,to further clarify the pivotal role of NNT promote the anoikis resistance in gastric cancer. ②Identify whether NNT promote the anoikis resistance via enhances NADPH and activates GSH pathway to eliminate ROS. ③ NNT was known couple hydride transfer from NADH to NADP+.This study will demonstrate the soure of NADH whether come from glucose or/and fatty acid? This study will demonstrate the antioxidant effect and mechanism of NNT in the anoikis resistance of gastric cancer.