纤维粘连蛋白EDA片段抑制线粒体自噬促进结肠癌有氧糖酵解的作用及机制研究

Aerobic glycolysis is one of the most important metabolic phenotypes and progression in tumors, and its mechanism is not fully clarified. Previous studies in our group have confirmed that the extra domain A (EDA) segment of fibronectin significantly promotes the proliferation and metastasis of colon cancer, but it is not clear whether EDA is involved in the regulation of aerobic glycolysis. Our preliminary results show that the EDA expression was significantly positively correlated with aerobic glycolysis and invasive phenotype in colon cancer. Furthermore, EDA can interact with PINK1/Parkin which is one of key molecules of mitophagy. This interaction between EDA and PINK1/pankin is key factors of resulting in mitophagy abnormalities and glycolysis enhancement. So, we speculate that EDA inhibits PINK1/Parkin signaling activity and leads to mitophagy disorders, which causes accumulation of dysfunctional mitochondria and then aerobic glycolysis is enhanced. Subsequently, it promotes the malignant progression in colon cancer. This project is intended to further study by using colon cancer cell model which EDA is overexpressed or knockdowned, colon cancer transgenic mouse model of EDA (hybrid EDA transgenic mice and APCmin/+ mice colon adenoma), colon cancer tissue microarray and the public databases of colon cancer patients. The correlation between EDA expression and aerobic glycolysis and malignant phenotype in colon cancer will be analyzed. Furthermore, we will explore the mechanism that EDA blocks mitophagy through inhibiting PINK1/Parkin signaling activity, and then damages the synthesis and function of mitochondria, so promotes aerobic glycolysis in colon cancer. And we will explore the possibility of anti EDA therapy using the tumor bearing nude mice model and transgenic mouse model. This study will present a new explanation for the fibronectin EDA promoting cancer progression from the viewpoint of glucose metabolism reprogramming. It can provide theoretical and experimental basis of clinical use of EDA as colon cancer precise diagnosis and treatment (tumor molecular classification, targeted therapy).

有氧糖酵解是肿瘤最重要代谢表型和恶性进展的重要原因，其发生机制尚未完全阐明。本课题组既往研究证实，纤维粘连蛋白EDA片段显著促进结肠癌增殖转移，但EDA是否参与调控有氧糖酵解而产生促癌效应尚不清楚。前期预试验结果表明，EDA表达与结肠癌有氧糖酵解、侵袭表型呈显著正相关，且与线粒体自噬关键分子PINK1/Parkin存在蛋白间相互作用，是导致线粒体自噬异常、糖酵解增强的关键因素。因此推测：EDA抑制PINK1/Parkin信号活性导致线粒体自噬障碍，引起功能缺陷线粒体堆积、有氧糖酵解增强，从而促进结肠癌恶性进展。本项目拟采用EDA高低表达结肠癌细胞模型和转基因杂交小鼠模型，深入研究EDA调控PINK1/Parkin信号抑制线粒体自噬，进而促进结肠癌有氧糖酵解的作用及分子机制，并以移植瘤和转基因小鼠初步探讨抗EDA治疗的可能性，为以EDA为靶标的结肠癌分子分型和精准治疗提供新的理论和实验依据。

有氧糖酵解是肿瘤最重要代谢表型和恶性进展的重要原因，其发生机制尚未完全阐明。本项目采用EDA高低表达结肠癌细胞模型和转基因杂交小鼠模型，深入研究EDA调控PINK1/Parkin信号抑制线粒体自噬，进而促进结肠癌有氧糖酵解的作用及分子机制。本课题组证实纤维粘连蛋白EDA片段显著促进结肠癌增殖转移，EDA表达与结肠癌有氧糖酵解、侵袭表型呈显著正相关，且与线粒体自噬关键分子PINK1/Parkin存在蛋白间相互作用，是导致线粒体自噬异常、糖酵解增强的关键因素。EDA抑制PINK1/Parkin信号活性导致线粒体自噬障碍，引起功能缺陷线粒体堆积、有氧糖酵解增强，从而促进结肠癌恶性进展的具体机制。为EDA为靶标的结肠癌分子分型和精准治疗提供新的理论和实验依据。