本项目在前期研究证实小檗碱具有靶向肝细胞核因子HNF4α抗糖尿病功效的基础上，以“细胞能量代谢异常是2型糖尿病与恶性肿瘤共同的病理生理学基础”为切入点，结合抗2型糖尿病药物通过调控“代谢开关”而发挥抗肿瘤功效这一最新研究动态，提出“调控AMPK-HNF4α-WNT致瘤信号轴可能是小檗碱抗胃癌作用的关键靶向通路之一”的全新假说。本项目拟采用现代病理生理，生物化学，细胞分子生物学等技术，整体与离体实验相结合，机能与代谢检测相结合，深入系列研究AMPK-HNF4α-WNT信号轴与胃癌发生的相关性以及小檗碱抗胃癌作用的相关机制，为从细胞能量代谢角度寻找恶性肿瘤的治疗靶点提供新的思路，进而为研发以小檗碱为母核分子结构，具有“单靶点，多途径，多功效”的新型治疗特色且兼具抗糖尿病与抗肿瘤双重功效的天然植物类新药奠定理论基础，同时也初步揭示出中药“异病同治”的科学内涵。

Previous evidence has demonstrated the efficacy of berberine on type 2 diabetes mellitus (T2DM) targeting HNF4α. Recent researches have shown that Metformin, a widely used anti-diabetes drug, was found to inhibit cancer cell lines and xenograft growth through regulating ‘metabolic switch’. Given that the abnormal energy metabolism of cells contributes to T2DM and cancer，we hypothesize that regulating ‘metabolic switch’ AMPK-HNF4α-WNT signaling axis: a potentially targetable pathway for Berberine on Gastric Cancer? To test our hypothesis, we will establish xenograft (NCI-N87 and MKN45) mouse models and GC cell models. Experiments have been designed to examine the activity and expression of AMPK-HNF4α signaling axis in GC tumors models. The modern techniques including pathophysiology, biochemistry and cell molecular biology such as ELISA, flow cytometry, Real time PCR, immunohistochemistry, western blot, report (Luciferase) assay, and siRNA transfection will be performed in vivo and in vitro. The successful completion if the proposed research will illustrate the mechanisms of the anti-gastric cancer actions of berberine, based on which we will be able to develop a new treatment for cancers in view of cell energy metabolism. Additionally, our study will provide scientific rationale for the potential utility of new anti-diabetes and anti-carcinoma agents which possess molecular structure as berberine and the feature of “mono-target point, multi-pathway, multi-actions” in the clinical practice. At the same time, the proposed research will explain scientific connotation of traditional Chinese medicine at “treating different diseases with the same method or the same target”.