内质网蛋白ENPP1通过激活脂合成代谢通路驱动透明细胞肾癌恶性进展的分子机制研究

透明细胞肾细胞癌（ccRCC）是高发于我国的一种恶性肿瘤，组织学上具有脂肪累积的特征，然而，脂代谢对ccRCC恶性进展的生物学意义尚不明确。Insig-SCAP-SREBP通路是哺乳动物细胞控制脂从头合成的重要信号通路，通过免疫共沉淀和蛋白质谱鉴定，申请人发现内质网蛋白ENPP1与锚定蛋白Insig结合，可阻断Insig对SCAP/SREBP复合物的锚定作用，促进SREBP入核，在细胞核内SREBP作为转录因子激活参与脂从头合成通路的基因表达，促进ccRCC的恶性进展。本研究将进一步通过生化实验明确ENPP1调控脂合成代谢通路的分子机理，以及裸鼠原位移植瘤模型明确ENPP1在ccRCC恶性进展中的生物学功能。本研究的完成将能补充哺乳动物细胞脂合成分子调控通路的已有认识，有望揭示ccRCC恶性进展的代谢弱点，为开发治疗ccRCC的新型药物提供理论依据。

Clear cell renal cell carcinoma (ccRCC) is a malignant tumor with a high incidence in China. It is histologically characterized by fat accumulation. However, the biological significance of lipid metabolism in the malignant progression of ccRCC is still unclear. The Insig-SCAP-SREBP pathway is an important signal pathway for mammalian cells to control the fatty de novo synthesis. Through immunoprecipitation and protein mass spectra, the applicant found that the endoplasmic reticulum protein ENPP1 binds to the anchor protein Insig, blocks the anchoring effect of Insig on the SCAP/SREBP complex, and promotes SREBP to enter the nucleus. In the nucleus, SREBP acts as a transcription factor to activate the expression of genes involved in the lipid de novo synthesis pathway, and promote the malignant progression of ccRCC. In this study, further biochemical experiments will clarify the molecular mechanism of ENPP1 regulating lipid metabolism pathways, and the orthotopic xenograft model will clarify the biological function of ENPP1 in the malignant progression of ccRCC. The completion of this study will complement the existing understanding of the molecular regulation pathways of lipid synthesis in mammalian cells, reveal the metabolic weakness of the malignant progression of ccRCC, and provide a theoretical basis for the development of new drugs for the treatment of ccRCC.