MPC-1乙酰化修饰调控糖代谢影响胰腺癌生长和干性特征的机制

项目名称： MPC-1乙酰化修饰调控糖代谢影响胰腺癌生长和干性特征的机制

项目编号： No.81502018

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 崔玖洁

作者单位： 上海交通大学

项目金额： 19万元

中文摘要： 课题组既往研究报道，胰腺癌中丙酮酸氧化磷酸化降低，易于生成乳酸，促进了胰腺癌的生长和转移。丙酮酸线粒体转运蛋白-1（Mitochondrial Pyruvate Carrier-1，MPC1）是转运丙酮酸进入线粒体的关键因子。课题组预实验发现,MPC1在胰腺癌中表达降低，且恢复MPC1表达可抑制胰腺癌生长和干细胞成球。进一步机制研究发现，MPC1表达受蛋白乙酰化修饰调节，且SIRT介导去乙酰化可增加MPC1蛋白稳定性。课题组将以这些研究结果为基础，采用经典分子生物学和模式动物等方法，深入研究乙酰化修饰对MPC1蛋白稳定性和/或活性的调节，探讨SIRT介导MPC1去乙酰化的作用，明确MPC1乙酰化修饰通过调控糖酵解对胰腺癌生长和干性特征的影响，并在临床组织样本中验证，从而阐明MPC1在胰腺癌中表达和/或功能降低的机制及生物学效应，最终为胰腺癌诊疗策略制定和新靶点寻找提供依据。

中文关键词： 胰腺外分泌肿瘤；丙酮酸线粒体转运蛋白-1；组蛋白去乙酰化酶；乙酰化；干细胞

英文摘要： Our previously studies found that oxidative phosphorylation of pyruvate was decreased in pancreatic cancer. Pyruvate tended to forming lactate and promoted pancreatic cancer growth and metastasis. Recently, it was reported that Mitochondrial Pyruvate Carrier-1 (MPC1) was the key factor which mediated mitochondrial pyruvate entry. We studied MPC1 in pancreatic cancer for the first and found that the expression of MPC1 was significantly decreased in both pancreatic cancer cell lines and tissues, and restored expression of MPC1 led to suppressed pancreatic cancer growth, invasion, migration and stem cell maintain. Further studies showed that the suppressed expression of MPC1 in pancreatic cancer was regulated by acetylation and SIRT mediated deacetylation of MPC1 which might increase the stability of MPC1. Based on these important preliminary data, we will further demonstrate the molecular mechanism of acetylation on MPC1 stability and/or activity, analyze the role of SIRT in MPC1 deactylation, and measure the effect of MPC1 acetylation on pancreatic cancer growth and stemness via glycolysis in vitro and in vivo.

英文关键词： pancreatic cancer ;MPC1;SIRT;Acetylation;Stem Cell