MAPK/ERK通路对eMSCs/fMSCs干细胞亚群能量代谢的差异性调控在Hp致胃癌发生中的作用

The mechanism underlying contribution of the bone marrow-derived mesenchymal stem cells(MSCs) to Helicobacter pylori-associated gastric cancer remains controversial, even though the concept is quite novel. Houghton et al have shown that MSCs could repopulate the gastric epithelium and progress to cancer. However, recent data has demonstrated that carcinoma associated fibroblasts (CAFs) in stomach, which promote gastric cancer progression, originated from MSCs.These clear evidences raised a model that MSCs contribute to gastric cancer as both epithelial and mesenchymal phenotype. Our previous data have investigated that MSCs present as two difference phenotypes in vitro: epithelial-like MSCs(eMSCs) and fibroblast-like MSCs(fMSCs)showing different stem cell biology, which might give an explanation for the phenotypic plasticity of MSCs in gastric cancer. However, the regulation mechanism of eMSCs/fMSCs remains unknown. The chronic H.pylori infection could lead to low glutamine microenvironment in stomach. Notably, the glutamine metabolism, mainly regulated by MAPK/ERK signal,has been recently demonstrated to be involved in the regulation of methylation status of stem cells and further effect on stem cell biology. And most interesting, MAPK/ERK signal was differentially expressed in eMSCs/fMSCs. Therefore, we address the hypothesis that the differential expressed MAPK/ERK signal in eMSCs/fMSCs could progress to gastric cancer through differential regulation of the metabolism of eMSCs/fMSCs, the aberrant methylation status of Wnt signal / promoter of Twist1, and tumorigenicity of MSCs. The project aims to emphasis the differential regulation of metabolism on eMSCs/fMSCs in different stages of inflammation, metaplasia, neoplasia and H. pylori-associated gastric cancer. To understand the real pathophysiology regulation of microenviroment, metasbolism, phenotypes diversity of MSCs (eMSCs/fMSCs) in gastric cancer holds the insightful therapeutic potential for gastric cancer patients.

骨髓基质干细胞（MSCs）以上皮细胞及间质细胞两种不同形式参与幽门螺杆菌（Hp）相关胃癌发生的现象尚未能得到统一解释。本课题基于我们前期MSCs表型多态性的原创发现，借用EMT/MET参与肿瘤发生发展的模型，提出MSCs表型转化（eMSCs/fMSCs）参与胃癌发生的观点。但其调控机制尚不清楚。Hp慢性感染可以导致低谷氨酰胺微环境，而近期研究显示谷氨酰胺能量代谢参与干细胞生物学调控。本课题利用干细胞能量代谢关键调控信号MAPK/ERK在eMSCs/fMSCs中差异性表达的特点，在“炎症—癌前病变—胃癌发生”不同阶段，检测Hp感染对eMSCs/fMSCs能量代谢应答影响的异同，观察eMSCs/fMSCs三羧酸循环主要代谢产物水平，下游甲基化水平，干细胞生物特性及致瘤性改变的差异，试图探讨微环境、能量代谢在差异性调控两种不同MSCs亚群参与Hp相关胃癌发生中的作用机制，为胃癌的防治提供新思路。

我们的前期研究发现骨髓间充质干细胞（MSCs）以上皮细胞及间质细胞两种不同形式参与幽门螺杆菌（Hp）相关胃癌发生，但其具体调控机制尚不明确。研究发现，Hp感染可导致胃内低谷氨酰胺微环境，而近期研究显示谷氨酰胺能量代谢可参与干细胞生物学调控。为探索Hp慢性感染低谷氨酰胺微环境对不同亚型骨髓间充质干细胞的影响，第一部分，我们利用BMP-7体外诱导建立经典间质上皮表型转化（MET）模型，同时构建了体外Hp感染和GGT缺陷的Hp感染模型；第二部分，检测了eMSCs/fMSCs干细胞亚群在不同Hp干预下的三羧酸循环代谢产物a-酮戊二酸（a-KG）与琥珀酸盐的比值；第三部分，我们进一步研究了eMSCs/fMSCs干细胞亚群在Hp感染和GGT缺陷的Hp感染下的增殖能力、迁移能力和分化能力。并且在裸鼠体内建立胃癌细胞和eMSCs/fMSCs移植模型以及慢性幽门螺旋杆菌感染balb/c小鼠移植eMSCs/fMSCs模型，探讨eMSCs/fMSCs两种不同亚群对胃癌发生发展的作用。结果显示,Hp的GGT酶可导致低谷氨酰微环境，而低谷氨酰微环境可上调eMSCs/fMSCs的a-KG与琥珀酸盐比值，而对eMSCs/fMSCs亚群的调控存在差异性，fMSCs的比值显著高于eMSCs。同时，Hp的GGT酶所导致的低谷氨酰氨微环境会导致eMSCs/fMSCs亚群的增殖迁移分化及成瘤能力增强，而对fMSCs和eMSCs的影响也存在差异性。本研究进一步明确了MSCs参与Hp相关胃癌发生的机制，有望为寻找胃癌治疗靶点提供依据。

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