PLD1在胃癌中的生物学功能及其调控机制研究

PLD1作为调控机体脂质代谢的重要酶类，如何调节胃癌细胞生长的具体机制至今仍不清楚。我们前期实验发现PLD1在胃癌组织中高表达，并在营养缺乏条件下PLD1通过作用于PA，避开mTOR信号通路，改变溶酶体pH值及功能，调节线粒体ROS含量，调控细胞脂质代谢和能量代谢影响胃癌细胞生长。本项目拟在此基础上，从细胞水平通过PLD1抑制剂和基因沉默技术解析PLD1调控溶酶体膜上离子通道和pH值的具体机制，探讨PLD1调节溶酶体线粒体轴的原理，明确PLD1调控Lipin1及内质网应激的机制；从动物水平通过药物阻断方式证实抑制PLD1是否具有减缓小鼠移植瘤生长的作用，采用质谱技术检测PLD1干预前后体内脂质代谢相关产物的变化。进一步从人体水平分析PLD1在胃癌组织中的表达含量，阐明PLD1与人体胃癌发生、发展及预后的相关性和临床意义。通过本研究旨在为以PLD1为靶点的胃癌治疗提供新思路和理论基础。

As an important enzyme regulating lipid metabolism in the body, PLD1 is still unclear on how to regulate the proliferation of gastric cancer cells. Our previous experiments found that PLD1 is highly expressed in gastric cancer tissues, and in the nutrient stress condition PLD1 can affect gastric cancer cell proliferation by its enzymatic product PA but not mTOR signaling pathway. Meanwhile PLD1 can regulates cell lipid metabolism and energy metabolism by changes lysosomal pH value as well as mitochondrial ROS content. Based on this, from the cellular level the project aims to analyze the specific mechanism of PLD1 regulating ion channel and pH on lysosomal membrane through PLD1 inhibitor and gene silencing technology, and to explore the theory of PLD1 regulating lysosomal-mitochondrial axis, and to clarify the principle that PLD1 regulates Lipin1 and endoplasmic reticulum stress; from the animal level to verify whether the inhibition of PLD1 can slow the growth of transplanted tumor in mice by drug injection, and to detect changes of lipid metabolism related products in vivo before and after PLD1 inhibitor treatment by mass spectrometry, and to observe PLD1 how to affect autophagy pathway, lipid metabolism and tumor markers in gastric cancer; furthermore, the expression level of PLD1 in gastric cancer tissues was analyzed from human level, as well as the correlation and clinical significance of PLD1 with the occurrence, development and prognosis of human gastric cancer were elucidated. This study aims to provide a new idea and theoretical basis for the treatment of gastric cancer with PLD1 as the target.