Meng Sha-Sha, Gu Hong-Wei, Zhang Ting, Li Yu-Sang, Tang He-Bin
Laboratory of Hepatopharmacology and Ethnopharmacology, School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, China.
Department of Pharmacy, Wuhan Mental Health Center, Wuhan, China.
Front Oncol. 2023 Mar 2;13:1099624. doi: 10.3389/fonc.2023.1099624. eCollection 2023.
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer kind. According to recent research, a fatty liver increases the risk of hepatocellular cancer. Nevertheless, the AMPK signaling pathway is crucial. In addition, 5'-AMP-activated protein kinase (AMPK) is strongly linked to alterations in the tumor microenvironment, such as inflammation, hypoxia, and aging. The objective of this study is to evaluate the impact of the AMPK signaling pathway on the progression of fatty liver to HCC.
In this study, we established a mouse liver cancer model using high-fat diets and nano-nitrosamines (nano-DEN). In addition, we employed a transcriptomic technique to identify all mRNAs detected in liver samples at the 25th weekexpression of proteins linked with the LKB1-AMPK-mTOR signaling pathway, inflammation, aging, and hypoxia was studied in microarrays of liver cancer tissues from mice and humans. These proteins included p-AMPK, LKB1, mTOR, COX-2, β-catenin, HMGB1, p16, and HIF-1α.
Data were collected at different times in the liver as well as in cancerous and paracancerous regions and analyzed by a multispectral imaging system. The results showed that most of the genes in the AMPK signaling pathway were downregulated. expression was upregulated compared to control group but downregulated in the cancerous regions compared to the paracancerous regions. expression was downregulated in the cancerous regions. expression was upregulated in the cancerous regions. During liver cancer formation, deletion of LKB1 in the LKB1-AMPK-mTOR signaling pathway reduces phosphorylation of AMPK. It contributed to the upregulation of mTOR, which further led to the upregulation of HIF1α. In addition, the expression of β-catenin, COX-2, and HMGB1 were upregulated, as well as the expression of p16 was downregulated.
These findings suggest that changes in the AMPK signaling pathway exacerbate the deterioration of disrupted energy metabolism, chronic inflammation, hypoxia, and cellular aging in the tumor microenvironment, promoting the development of fatty liver into liver cancer.
肝细胞癌（HCC）是最常见的原发性肝癌类型。根据最近的研究，脂肪肝会增加肝细胞癌的风险。然而，AMPK信号通路至关重要。此外，5'-AMP激活蛋白激酶（AMPK）与肿瘤微环境的改变密切相关，如炎症、缺氧和衰老。本研究的目的是评估AMPK信号通路对脂肪肝向HCC进展的影响。
在本研究中，我们使用高脂饮食和纳米亚硝胺（纳米DEN）建立了小鼠肝癌模型。此外，我们采用转录组技术来鉴定在第25周时肝脏样本中检测到的所有mRNA。在小鼠和人类肝癌组织的微阵列中研究了与LKB1-AMPK-mTOR信号通路、炎症、衰老和缺氧相关的蛋白质表达。这些蛋白质包括p-AMPK、LKB1、mTOR、COX-2、β-连环蛋白、HMGB1、p16和HIF-1α。
在肝脏以及癌组织和癌旁组织的不同时间收集数据，并通过多光谱成像系统进行分析。结果表明，AMPK信号通路中的大多数基因被下调。与对照组相比，其表达上调，但与癌旁组织相比，在癌组织中下调。其表达在癌组织中下调。其表达在癌组织中上调。在肝癌形成过程中，LKB1-AMPK-mTOR信号通路中LKB1的缺失会降低AMPK的磷酸化。这导致mTOR的上调，进而导致HIF1α的上调。此外，β-连环蛋白、COX-2和HMGB1的表达上调，以及p16的表达下调。
这些发现表明，AMPK信号通路的变化加剧了肿瘤微环境中能量代谢紊乱、慢性炎症、缺氧和细胞衰老的恶化，促进了脂肪肝向肝癌的发展。
