单胺氧化酶MAOA介导的神经递质降解调控Warburg效应抑制胃癌进展的分子机制研究

Warburg效应作为一种典型的代谢重组方式，参与多种恶性肿瘤的发生发展，而其在胃癌演进中的具体作用尚不明确。申请者通过前期生物信息学分析和胃癌组织样本转录组测序发现，MAOA参与调控胃癌Warburg效应，功能实验表明MAOA具有抑制糖酵解和肿瘤恶性生物学行为作用。KEGG富集分析发现，MAOA表达与P53通路活化程度呈正相关，推测MAOA基于P53通路介导调控胃癌Warburg效应。通过生信预测，初步发现P53启动子区存在CREB结合位点，以及MAOA启动子区存在P53结合位点，故可能存在反馈环MAOA-NE-PKA/CREB-P53-MAOA。本课题拟在前期研究基础上：①探讨MAOA在胃癌细胞系的功能；②阐明上述反馈环调控Warburg效应的分子机制；③分析MAOA表达临床意义及其调控糖酵解酶作为治疗靶点的可能，以期从肿瘤代谢与神经递质角度，为胃癌临床治疗提供新的思路和方向。

As a typical metabolic recombination mode, Warburg effect is involved in the occurrence and development of a variety of malignant tumors, and its specific role in gastric cancer progression is unclear. Through preliminary bioinformatics analysis and gastric cancer tissue samples transcriptome-sequencing, applicants have found that monoamine oxidase MAOA is involved in regulating the Warburg effect of gastric cancer. Functional experiments show that MAOA significantly inhibits glycolysis metabolism and tumor malignant biological behavior by degrading the neurotransmitter NE. After KEGG enrichment analysis, we found that the expression of MAOA in gastric cancer cell lines was positively correlated with the degree of the P53 pathway activation. It is speculated that MAOA is mediated by the P53 pathway to further regulate the Warburg effect of gastric cancer. According to the prediction of the transcription factor website, it is found that the MAOA promoter region holds a binding site of transcription factor P53 to regulate its expression. Therefore, it may exist a feedback loop MAOA-NE-P53-MAOA. Based on previous researches, the following contents could be completed. ① explore the functional role of MAOA in the malignant biological behavior of gastric cancer cell lines; ② elucidate the molecular mechanism of the above MAOA-NE-P53-MAOA feedback loop for Warburg effect regulation; ③ analyze the clinical significance of MAOA expression and the possibility of regulating glycolytic enzymes as therapeutic targets for gastric cancer. As a result, it will provide new ideas and directions for the clinical treatment of gastric cancer from the perspective of tumor metabolism and neurotransmitters.