二甲双胍通过FoxO1对肝癌18F-FDG摄取增强作用研究及其机制探索

Liver cancer is seriously affected in the performance of PET due to its low level of 18F-FDG uptake. The main reason is the overexpression of glucose-6-phosphatase (G6Pase) and P-glycoprotein (P-gp) of liver cancer cells. Previous studies suggest that metformin inhibits transcriptional expression of these two molecules, and enhance colon 18F-FDG uptake. Meanwhile, FoxO1 plays an important role in the transcriptional regulation of these two molecules in the process. Our team previously found that metformin preliminary experiments can significantly improve the 18F-FDG uptake in liver cancer in vitro and in vivo, but the underlying mechanism and the relationship between metformin and FoxO1 is still unclear. This project focuses on whether metformin can improve liver cancer 18F-FDG PET imaging and the molecular mechanisms associated with metformin, FoxO1 and two key scientific issues, through performing 18F-FDG PET imaging studies of liver cancer as well as verifying metformin metformin-AMPKPI3K/Akt-FoxO1 pathway. This project can not only provide a new alternative to improve the situation of low uptake of 18F-FDG liver cancer, enhancing the value of PET in the early diagnosis of liver cancer, but also can provide evidence for the full reveal of oncology function of metformin and FoxO1 in the metabolism, biological behavior and drug resistance of liver cancer.

肝癌由于其对18F-FDG的低摄取而严重影响了PET对其的探测效能，主要原因是肝癌细胞中葡糖-6-磷酸酶（G6Pase）及P-糖蛋白（P-gp）高表达。既往研究表明，二甲双胍可抑制上述两个分子的转录表达，并可提升结肠癌的18F-FDG摄取；同时，FoxO1在上述两个分子的转录调控过程中扮演着重要角色。本课题组预实验发现二甲双胍可在体外和体内显著提升肝癌18F-FDG摄取，但机制不明。本课题针对二甲双胍能否对肝癌18F-FDG PET显像实现增强及其与FoxO1相关的分子机制这两个关键科学问题，通过对二甲双胍干预肝癌的18F-FDG PET显像研究以及对二甲双胍-AMPK-PI3K/Akt-FoxO1通路的验证，从而不仅为改善肝癌18F-FDG低摄取的现状、提升PET在肝癌早期诊断中的应用价值提供新的备选方案，更是为全面揭示二甲双胍与FoxO1在肝癌代谢、耐药等生物学行为方面的作用奠定基础。

肝癌的早期诊断是影像学的挑战性问题。肿瘤早期诊断利器PET/CT因18F-FDG在肝细胞肝癌中摄取不佳，而在NCCN指南中明确不推荐作为肝癌的诊断手段，极大限制了PET/CT在肝癌中的应用。本研究针对肝癌FDG低摄取的主因G6Pase，提出二甲双胍可通过FoxO1下调G6Pase从而提升肝癌FDG摄取的科学假说，在体外和在体研究中证实了二甲双胍可通过转录下调G6Pase水平而提升肝癌FDG摄取，且FoxO1是肝癌FDG摄取调控的转录因子和作用靶点。本研究为临床提升肝癌的18F-FDG摄取提供了Met干预这一备选方案，并证实了FoxO1这一干预靶点。