AKT2-PKM2信号通路异常活化介导肿瘤微环境代谢重塑促进肝脏癌变

Liver is a major organ for metabolism and detoxification. Chronic liver injury initiates a vicious cycle of hepatocyte death, inflammation, and fibrosis that eventually leads to cirrhosis and cancer. This pathological process often involves hepatocytes, macrophages, and stellate cells in tumor microenvironment. By integrating nutrient signals, PI3K/PTEN-AKT-mTOR signaling pathway modulates cell metabolism, autophagy, cell growth and proliferation to maintain organismal homeostasis. It is aberrantly activated in more than 50% liver cancer due to various alterations of proto-oncogenes and tumor suppressors. We found that hepatocyte knockout of Pten led to AKT2-mTOR-PKM2 cascade activation, steatohepatitis, and accelerated transgenic HBV-mediated liver cancer in mice. Metabolic regulator, AKT2, is mainly expressed in the liver. AKT2E17K is an active mutant of AKT2 in patients with metabolic disorder. Hepatocyte AKT2E17K knock-in mice develop steatosis and are susceptible to diethylnitrosamine (DEN)-induced liver cancer. Conventional knock-in mice with PKM2 overexpression are also vulnerable to DEN treatment and develop liver cancer much sooner than control mice. Therefore, we propose that AKT2 activation potentiates mTOR and consequently stimulates PKM2 expression. This boosted signaling cascade may reprogram cell metabolism and alter the microenvironment, and in return drive cancer progression. We plan to generate mice with PKM2 overexpression in hepatocyte, macrophage and stellate cell using conditional PKM2 knock-in mice. These mice will be subjected to DEN treatment for hepatocarcinogenesis. Along with our hepatocyte AKT2E17K mice, we will study the interplay of metabolism and immune response in tumor microenvironment on liver tumorigenesis of these mice. This study may help us gain further insights into pathological mechanism of liver cancer and identify targets for intervention.

肝脏是主要代谢和解毒器官，代谢异常是慢性炎症的重要诱因，慢性肝损伤、炎症、纤维化和肝硬化是微环境中介导肿瘤的关键因素。PI3K/PTEN-AKT-mTOR信号通路调节机体新陈代谢，维持机体的稳态，50%以上的肝癌有这个通路的异常活化。我们发现，肝细胞敲除PTEN引起 AKT2-mTOR-PKM2信号通路活化、脂肪肝，加重HBV转基因小鼠肝癌的进程;肝细胞AKT2活化导致脂肪肝，加快二乙基亚硝胺(DEN)诱导肝癌；DEN可快速诱发全身PKM2过表达PKM2敲入小鼠产生肝癌。我们认为AKT2活化通过激活mTOR，上调PKM2,代谢重塑，炎性细胞重编程，加重肝脏的损伤和炎症，促进肝癌进程。我们将分别构建肝细胞、巨噬细胞和星状细胞PKM2敲入小鼠，DEN诱发肝癌；研究PKM2过表达和AKT2活化小鼠肝癌微环境内代谢重塑与免疫重编程，阐明肝癌发生机制，寻找肝癌的治疗方法。

PTEN在大约一半的肝癌中表达降低或缺失，Pten缺失和乙肝病毒（HBV）转基因协同加重小鼠肝损伤、炎症和肝癌发展，敲除GP73减轻了这些病变。因此，抑制GP73是一种有前途的肝癌治疗策略。. 高脂饮食激活小鼠肝脏AKT2。活化的AKT2诱导肝脂肪变性、炎症和肝细胞癌。抑制SREBP1，SCD1或Kupffer细胞可减轻AKT2活化小鼠的肝脏脂肪变性和炎症，减缓肝癌发生，因此SREBP1/SCD1激活导致的肝脏脂肪变性和炎症的增强对AKT2活化诱导肝细胞癌（HCC）至关重要。干预脂肪变性和炎症可能有益于AKT2活化HCC的治疗。. β-catenin是包括肝母细胞瘤和肝细胞肝癌在内的肝脏肿瘤发展的主要驱动因素。AKT2介导的CAD磷酸化是β-catenin诱导的嘧啶合成和肝癌发生的必要条件。靶向β-catenin, AKT2和/或嘧啶合成可治疗β-catenin突变型肝癌，为治疗肝癌提供了一种新策略。.