Evaluations of Apolipoprotein E on the Pathological Role in Lung Cancer and the Application in Early Prediction of Clinical Outcome

High-calories cultural diets and lack of exercise are major causes resulting in growing problems of obesity and hyperlipidemia. In addition to the cardiovascular diseases, numerous evidences have suggested that hyperlipidemia will increase the risk suffering the cancers. Cancer is a top ten leading causes of death in Taiwan. Among that, the incidence rate of lung cancer ranked first. Our preliminary study demonstrated that hyperlipidemia enhanced lung tumor growth, and apolipoprotein E (Apo E) protein was highly expressed within the tumor. To date, they are still unclear in the pathological mechanisms and molecular regulations in ApoE-promoting effects on growth and metastasis of lung cancer cells as well as in hyperlipidemia-enhanced lung tumor growth. Besides, the relationship and regulatory mechanisms should also be further clarified whether angiogenesis closely associated with tumor growth and metastasis is involved in the process of hyperlipidemia-enhanced lung tumor growth as well as ApoE is involved them. Accordingly, this project will be divided into three stages to clarify the several questions between hyperlipidemia and lung cancer. At stage I, cDNA microarray will be applied on cellular model to investigate the pathological mechanisms in hyperlipidemia-enhanced growth of lung cancer cells, to examine impacts and regulations of hyperlipidemia on vascular endothelial growth factor (VEGF)-mediated pathway and angiogenesis, and to clarify the possible reasons and molecular mechanisms involved in up-regulation of ApoE within lung tumor by using ApoE promoter assay. On the other hand, ApoE knockou in the lung cancer cells and vascular endothelial cells will be used to evaluate the possible role and regulatory mechanisms of ApoE on cell growth and metastasis of lung cancer cells as well as angiogenesis. At stage II, lung cancer-bearing hyperlipidemic mouse model (ApoE-/- mice) will be applied to verify the experimental results regarding hyperlipidemia-modulated molecular regulations and expression profile on lung cancer cell growth and angiogenesis. In addition, the lipid-lowering drug will be used alone or combined with clinical chemotherapy drug to evaluate its feasibility as an adjuvant chemotherapy in clinical treatment of lung cancer. At stage III, the study will be focused on clinical examination and analysis of lung cancer specimens. The early-stage lung cancer specimens obtained from the Taiwan Biobank database will be used to examine the expression and the genotype of ApoE, which coordinated with medical record analysis will help us to evaluate whether ApoE can be applied as an early-stage biomarker for predicting clinical outcome of lung cancer. The project achievements will help to better understand the relationship and the regulatory mechanisms between hyperlipidemia and lung cancer as well as to explore the potential novel therapeutic targets for applying in the development of new anti-cancer drugs in the future. Besides, it will provide better therapeutic interventions based on individual situation of patients suffering from lung cancer through development of early-stage biomarker and efficacy validation of adjuvant chemotherapy.