肿瘤相关成纤维细胞通过BTBD19/GAD1轴调控β-丙氨酸合成促进胃癌转移的机制研究

肿瘤相关成纤维细胞（CAFs）与胃癌转移密切相关，但其调控机制仍未完全阐明。我们前期发现CAFs中β-丙氨酸含量升高，并可代谢为谷氨酰胺分泌至微环境中促进胃癌细胞TCA循环和转移；下调BTBD19抑制β-丙氨酸合成相关酶GAD1的表达和启动子琥珀酰化；GAD1启动子可结合KAT2A，并含有TEAD4的潜在结合位点。本项目提出如下假设：CAFs中BTBD19通过募集KAT2A致GAD1启动子琥珀酰化，促进TEAD4介导的GAD1转录激活，β-丙氨酸合成增加并代谢成谷氨酰胺分泌至微环境中，促进胃癌细胞TCA循环和转移。本项目将探讨：1）β-丙氨酸在胃癌中的含量及临床意义；2）CAFs通过β-丙氨酸促进胃癌细胞TCA循环和转移的作用和机制；3）CAFs通过BTBD19/GAD1促进β-丙氨酸合成的调控机理。本项目研究成果可为胃癌转移的防治提供新的靶点和思路。

Cancer-associated fibroblasts (CAFs) are closely related to gastric cancer metastasis, but the regulatory mechanism is still not fully elucidated. We .previously found that the content of beta-alanine in CAFs is increased in gastric cancer. Beta-alanine can be metabolized to glutamine and secreted into the microenvironment to promote the TCA cycle and metastasis of gastric cancer cells. Down-regulation of BTBD19 in CAFs significantly inhibits GAD1, an enzyme related to beta-alanine synthesis，expression and its promoter succinylation. GAD1 promoter can bind KAT2A and contains TEAD4 predicted binding site. This project proposes the following hypothesis: BTBD19 in CAFs induces succinylation of GAD1 promoter by recruiting KAT2A to promote TEAD4-mediated GAD1 transcriptional activation, thus beta-alanine synthesis is increased and metabolized into glutamine which is secreted into the microenvironment to promote gastric cancer cell TCA cycle and metastasis. This project will explore: 1) the content and clinical significance of beta-alanine in gastric cancer; 2) the role and mechanism of CAFs in promoting TCA cycle and metastasis of gastric cancer cells through beta-alanine; 3) the regulatory mechanism of beta-alanine synthesis in CAFs through BTBD19 /GAD1 axis. The results of this project can provide new targets and ideas for the prevention and treatment of gastric cancer metastasis.