代谢酶PCK2促进胃癌转移的功能及调控机制研究

肿瘤转移是治疗失败的主要原因。肿瘤转移与细胞代谢异常息息相关。我们前期研究发现磷酸烯醇式丙酮酸羧激酶2(PCK2)随着胃癌转移表达逐步升高，过表达PCK2促进胃癌细胞侵袭转移，提示PCK2具有促转移功能，但其具体机制尚不明确。代谢组学数据显示PCK2的过表达致使癌代谢物D-2-HG升高，提示PCK2参与了截短型三羧酸循环（truncated TCA cycle）。进一步研究显示PCK2受到潜在转录因子FOXJ2的调节,且两者在胃癌中表达呈正相关，故我们推测FOXJ2调控PCK2激活癌代谢物D-2-羟基戊二酸（D-2-HG）促进胃癌转移。本课题拟通过分子生物学手段和体内外实验研究PCK2的作用机制和调控机制，阐明“FOXJ2-PCK2-D-2-HG”轴在胃癌转移中的作用，丰富胃癌转移理论和寻找干预胃癌转移的潜在治疗靶点。

Tumor metastasis is the main cause of drug-resistance and poor outcome of cancer. Metastasis is closely related to abnormal cell metabolism. Our previous study found that the expression level of phosphoenolpyruvate carboxykinase 2(PCK2) was increased in the metastatic gastric cancer cells, and overexpression of PCK2 promoted the invasion of gastric cancer cells, suggesting that PCK2 has the function of promoting metastasis. However, the underlying mechanism is still unclear. Metabolomic data showed that overexpression of PCK2 led to increased accumulation of d-2-Hydroxyglutarate (D-2-HG), suggesting that PCK2 participated in truncated TCA cycle. Further studies showed that PCK2 was regulated by a potential transcription factor FOXJ2. Therefore, we speculated that activated PCK2 by FOXJ2 promoted gastric cancer metastasis through accumulation of oncometabolite D-2-Hydroxyglutarate. In this study, multiple technologies will be used to study the functional mechanism of PCK2 and the regulatory effect of FOXJ2 on PCK2. The work will clarify the role of "FOXJ2-PCK2-D-2-HG" axis in gastric cancer metastasis and enrich the theory of metastasis. Our study will be helpful in searching potential therapeutic targets to intervene gastric cancer metastasis.