内质网应激致肝癌形成的机制研究

Peroxisomal acyl-coenzyme A oxidase 1 (Acox1) is the first enzyme in the fatty acid β-oxidation pathway. Global deficiency of Acox1 causes severe metabolism syndromes including fatty liver change and hepatocarcinogenesis. Our previous study showed that endoplasmic reticulum stress (ERS) progressively increases in Acox1-/- mice, which indicates that ERS may play important roles during hepatocarcinogenesis. However, whether ERS can directly cause carcinogenesis is still unknown. In this study, we will further generate Acox1 liver specific deficient mice (Acox1?Liv) to study whether these mice also develop liver cancer caused by ERS and its detailed mechanisms and whether change of ERS is associated to the hepatocarcinogenesis and development. Since p8 has been shown to be involved in ERS-associated carcinogenesis in Acox1-/- mice, we will also generate p8-/- Acox1?Liv double deficient mice to further study the central importance of p8 in ERS-induced hepatocarcinogenesis, which will provide new theoretical and experimental data for cancer therapy

乙酰辅酶A氧化酶(Acox1)是微粒体长链脂肪酸氧化的限速酶，小鼠Acox1缺失(Acox1-/-)可导致严重的全身代谢综合症，包括脂肪肝和肝癌等。我们先前的研究显示，内质网应激(ER stress, ERS)在Acox1-/-肝脏中随年龄的增大而增强，提示ERS可能在肝脏肿瘤形成中发挥重要作用，但是否起主导作用还不清楚。本研究将构建Acox1肝脏特异性缺失(Acox1?Liv)小鼠，深入研究肝脏Acox1特异性缺失对ERS诱导肝癌形成的病理机制，通过控制ERS的强度，研究ERS和肝癌发生和发展的相关性；并将进一步构建Acox1和p8双缺陷小鼠(p8-/-Acox1?Liv)，观察其是否产生肿瘤，从而确定p8在ERS诱导肝癌发生中的核心作用，为肝癌的治疗提供新的理论和实验依据。

本研究结果表明：1、Acox1转基因鼠呈现脂肪肝症状；2、Acox1转基因鼠呈现肝纤维化表现；3、Acox1转基因鼠呈现高脂血症；4、Acox1转基因鼠呈现II型糖尿病表现；5、内质网应激（ER stress）在代谢疾病中发挥重要的作用。