C1QBP通过DLAT调节能量代谢在肾癌增殖及转移中的作用机制研究

Abnormal energy metabolism plays an important role in cancer progression. In our previous study, we reported that in contrast to other types of tumors, complement component 1 Q subcomponent-binding protein (C1QBP) negatively regulated the proliferation and metastasis of renal cell carcinoma (RCC). However, the underlying molecular mechanism of C1QBP regulating RCC progression has not been well elucidated. In our preliminary studies, a systematic screening of the C1QBP interacting proteins was conducted by quantitative proteomics method. The results showed that C1QBP could bind with dihydrolipoyl transacetylase (DLAT). Meanwhile, the knockdown of C1QBP inhibited the activity of pyruvate dehydrogenase complex and enhanced the cell glucolysis. Thus, we hypothesize that C1QBP can regulate the proliferation and metastasis of RCC by regulating energy metabolism through interacting with DLAT. We will aim to investigate the interaction between C1QBP and DLAT and their roles in regulating downstream genes expression; The cellular function of C1QBP in regulating RCC cell energy metabolisms will be verified. In addition, RCC cell and xenograft mouse model will be used to identify the effects of C1QBP on regulating RCC proliferation and metastasis through modulating energy metabolism in vitro and in vivo. Furthermore, C1QBP and DLAT expressions in RCC clinical specimens will be examined and their relationship with RCC prognosis will be analyzed. Last, we will build C1QBP networks with the interaction proteins and metabolic spectrum in RCC. This study will shed light on a new mechanism that C1QBP regulates cell energy metabolism and RCC progression.

异常能量代谢在肿瘤发生发展中起重要作用。本课题组既往研究发现，与在其它肿瘤中的作用相反，C1QBP表达下调可促进肾癌的增殖及转移，然而C1QBP调控肾癌进展的机制尚不清楚。前期工作通过蛋白质组学技术发现C1QBP与DLAT存在相互作用，C1QBP降表达可抑制丙酮酸脱氢酶复合体的活性，促进肾癌细胞糖酵解。由此我们推测C1QBP通过DLAT调节肾癌细胞能量代谢，进而调控肾癌的增殖及转移。本项目将深入研究C1QBP与DLAT的相互作用以及调控下游基因表达的功能和机制；阐明C1QBP对肾癌细胞能量代谢及产能途径的变化影响；运用细胞学及原位肾癌移植瘤模型考察C1QBP通过调节能量代谢调控肾癌的增殖及转移；结合临床病理资料检测C1QBP、DLAT等蛋白在肾癌标本中的表达及预后分析；并进一步构建C1QBP相互作用的蛋白网络及代谢谱。本项目为解析C1QBP在调控肿瘤代谢和进展中的新功能与相关机理奠定基础。

异常能量代谢在肿瘤发生发展中起重要作用。本项目通过蛋白质组学及免疫共沉淀发现C1QBP与DLAT在肾癌细胞中存在相互作用，并检测了两者共定位及作用的结构域位点；完成了C1QBP在肾癌细胞中代谢组学的检测分析，构建了C1QBP相互作用蛋白网络；在临床肾癌标本中检测分析了C1QBP、二氢硫辛酸转乙酰基酶（DLAT）、黄嘌呤脱氢酶（XDH）与疾病进展及预后的关系；探究了C1QBP与DLAT的相互作用以及调控下游基因表达的功能和机制；阐明了C1QBP与DLAT相互作用调控肾癌细胞糖代谢、C1QBP调控XDH影响次黄嘌呤分解代谢及凋亡的机制；通过构建原位肾癌移植瘤模型考察了C1QBP调节糖代谢及嘌呤代谢调控肾癌的增殖及转移；初步发现了C1QBP在肾癌细胞中对脂肪代谢的影响。本项目为解析C1QBP在调控肿瘤代谢和进展中的新功能与相关机理奠定基础。