C/EBPδ/Slug/Lox1信号轴促进肺腺癌侵袭转移的作用机制研究

The incidence and mortality of lung cancer rank first among all cancers. Lung metastasis is the leading cause for high mortality of lung cancer patients. Cancer cells undergo significant lipid metabolic reprogramming to ensure sufficient energy supply for survival and progression, while epithelial-mesenchymal transition (EMT) is a pathophysiological event during cancer metastasis. However, how cancer cells integrate lipid metabolism with EMT signaling is not well understood. Our findings show that C/EBPδ, a critical lipid metabolic regulator, is significantly upregulated at the early stage of TGF-β induced EMT. Further study shows that C/EBPδ promotes cell migration and lung adenocarcinoma metastasis both in vitro and in vivo. Importantly, RNA high-throughput sequencing data shows that C/EBPδ involved in both lipid metabolic and EMT gene networks. Further results show that C/EBPδ enhanced oxLDL uptake and regulated oxLDL receptor-1 (Lox1) expression. C/EBPδ also activated Slug, a classic EMT transcription factor. In addition，Slug promotes oxLDL uptake and Lox1 expression. We put forward the hypothesis that C/EBPδ promotes cancer metastasis through significant oscillations in both lipid metabolic and EMT gene networks . This project will focus on the mechanistic regulation of C/EBPδ/Slug/Lox1 axis (networks) in the process of lung cancer metastasis,employing both in vitro and in vivo experiments and pathological analysis. Our findings may provide theoretical basis and potential theraputical targets for lung adenocarcinoma treatment.

肺癌的发生率和死亡率高居所有癌症之首，癌细胞侵袭转移是其高致死率的主要原因。脂代谢能为侵袭转移提供物质保障，而EMT是侵袭转移过程中的重要事件。然而，癌细胞能否整合脂代谢和EMT信号通路最终促进肺癌侵袭转移尚不明确。我们发现，脂代谢关键转录因子C/EBPδ在肺腺癌细胞EMT的早期表达量显著增加，体内外实验显示它能促进细胞迁移和肺腺癌侵袭转移。RNAseq数据显示C/EBPδ同时参与脂代谢和EMT信号通路，C/EBPδ既能促进oxLDL的摄取和其受体Lox1的表达，又能促进EMT转录因子Slug的转录，而Slug也影响oxLDL通路。我们提出假说，C/EBPδ通过整合EMT和脂代谢信号通路而促进肺腺癌侵袭转移。本项目将在现有研究基础上，通过体内外实验结合病理组织分析，重点研究C/EBPδ/Slug/Lox1信号轴(网）在肺腺癌侵袭转移中的作用机制，将为肺腺癌的临床治疗提供理论指导和药物靶点。

肺癌的发生率和死亡率高居所有癌症之首，癌细胞侵袭转移是其高致死率的主要原因。脂代谢能为侵袭转移提供物质保障，而EMT是侵袭转移过程中的重要事件。然而，癌细胞能否整合脂代谢和EMT信号通路最终促进肺癌侵袭转移尚不明确。在本项目资助下，我们首先按照计划明确了C/EBPδ通过C/EBPδ/Slug/lox1信号轴整合EMT和脂代谢通路，最终促进肺腺癌侵袭转移，并阐明其具体调节方式，为肺癌临床诊断治疗提供潜在药物靶点和理论依据。相关研究发表在Oncogene杂志上。除此之外，由于肥胖和肝脏相关疾病严重威胁人类生存和健康，我们在本项目支持下，进行了肝脏和脂肪方面的拓展研究，肝脏相关研究成果介绍了内质网应激以及N6 甲基腺苷读取器 YTHDC2在非酒精性脂肪性肝病发生发展过程中的作用，相关研究发表在Hepatology、Journal of Hepatology杂志上，脂肪代谢方面的研究主要关于温和热刺激和阿奇霉素等环境污染物对脂肪组织产热和肥胖的影响，相关研究工作以研究论文的形式发表在Cell、Theranostics及Front in physiology;Frontier in Endocrinology杂志上。另外，在项目支持下，培养博士研究生1名，硕士研究生2名。