PrPc通过MGr1-Ag/37LRP介导胃癌多药耐药的新机制

With the support of previous NSFC, our study firstly showed that PrP was upregulated and promoted multidrug resistance (MDR) in gastric cancer, partially through PI3K/Akt pathway. However, PrPc is lacking of the intracellular domain. How can it transduce the signal and mediate gastric cancer MDR worth further investigation. MGr1 is the antibody developed in our lab, which played important roles in gastric cancer MDR. It’s known that MGr1-Ag/37LRP has participated in multiple signal pathways in gastric cancer MDR, through directed binding with FAK and activation PI3K/Akt signal pathway. Meanwhile, it would interact with PrPc directly. Our recent work showed that combined significance of PrPc and MGr1-Ag/37LRP in gastric cancer survival (Int J Cancer，2014). Meanwhile, MGr1-Ag/37LRP was found co-located and interacted with PrPc to mediate MDR of gastric cancer. This project will further proved this co-localization, function and interaction sites. With the knockdown technique, we’ll also study on the effect and mechanism of PrPc mediated gastric cancer MDR by interrupting the two proteins interaction. This study is the deep and extensively research based on previous study, which will not only show part of biological function of PrPc, but also shed light on mechanism of in gastric cancer MDR.

在青年基金资助下，本课题组在国际上率先发现缺氧诱导PrPc在胃癌中表达增高，通过PI3K/Akt通路介导胃癌的多药耐药。但是PrPc没有胞内段，如何传递信号，介导胃癌耐药机制不明确。MGr1是本实验室前期发现胃癌耐药密切相关的抗体，其抗原MGr1-Ag/37LRP具有跨膜段，可与FAK直接作用激活PI3K/Akt信号通路参与胃癌耐药，且已证实可以和PrPc相互作用。本课题组近期工作证明两者协同对胃癌预后判断具有重要意义（Int J Cancer，2014），此项目在上述工作的基础上，明确PrPc与MGr1-Ag/37LRP在胃癌组织和细胞中的表达相关性，研究两者的相互作用及位点，通过干预手段明确PrPc通过MGr1-Ag/37LRP诱导胃癌多药耐药的影响和机制。本项目是课题组长期研究的深入，有助于进一步揭示PrPc及MGr1-Ag/37LRP的生物学功能，进一步阐明胃癌化疗耐药的机制。

在既往青年基金资助下，课题组在国际上率先发现缺氧诱导PrPc在胃癌中表达增高，通过PI3K/Akt通路介导胃癌的多药耐药。但是PrPc没有胞内段，如何传递信号，介导胃癌耐药机制不明确。MGr1是本实验室前期发现胃癌耐药密切相关的抗体，其抗原MGr1-Ag/37LRP具有跨膜段，可与FAK直接作用激活PI3K/Akt信号通路参与胃癌耐药，且已证实可以和PrPc相互作用。本课题通过临床标本检测，PrPc可以与细胞层黏连蛋白（37LRP）在胃癌组织和细胞中存在共定位，并且直接相互作用，通过PI3K/Akt通路抑制胃癌细胞凋亡，参与胃癌的发生发展(Oncotarget, 2017)。通过带有预后信息的胃癌组织标本免疫组织化学和相关性分析，发现PrPc高表达的胃癌预后差，MGr1-Ag/37LRP阳性表达的胃癌组织预后不佳， 如果联合PrPc和MGr1-Ag/37LRP双阳性表达的胃癌预后更差(Int J Cancer, 2014)。本项目是课题组长期研究的深入，有助于进一步揭示PrPc及MGr1-Ag/37LRP的生物学功能，进一步阐明胃癌化疗耐药的机制。