Wu Yonglin, Rong Xingyu, Pan Miaomiao, Wang Tongyao, Yang Hao, Chen Xiejiu, Xiao Zhenming, Zhao Chao
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College and National Clinical Research Center for Aging and Medicine, Shanghai Medical College, Huashan Hospital, Fudan University, Shanghai, China.
Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai, China.
Front Cell Dev Biol. 2022 May 23;10:840171. doi: 10.3389/fcell.2022.840171. eCollection 2022.
Liver cancer has a high mortality rate. Chronic inflammation is one of the leading causes of hepatocellular carcinoma. Recent studies suggested high levels of trimethylamine N-oxide (TMAO) may correlate with increased risk of inflammatory-induced liver cancer. However, the mechanisms by which TMAO promotes liver cancer remain elusive. Here, we established a model of inflammatory-induced liver cancer by treating Hepa1-6 cells and Huh7 cells with TNF-α. TMAO synergistically increased the proliferation, migration and invasion of Hepa1-6 cells and Huh7 cells in the presence of TNF-α. We conducted bulk RNA-Seq of the TMAO-treated cell model of inflammatory Hepatocellular carcinoma (HCC) and evaluated the influence of the differentially expressed genes (DEGs) on clinical prognosis using Kaplan-Meier Plotter Database and Gene Expression Profiling Interactive Analysis (GEPIA) database. Univariate and multivariate Cox regression analyses of tumor microenvironment and DEGs were performed using Timer2.0. Upregulation of , and and downregulation of and were positively related to poorer overall survival in human liver cancer. Moreover, higher expression of and positively correlated with infiltration of neutrophils, which can promote tumor progression. experiments showed TMAO activates ILK/AKT/mTOR signaling via , and knocking down significantly reduced ILK/AKT/mTOR signaling and the tumorigenicity of Hepa1-6 cells and Huh7 cells. Collectively, our results suggest the gut microbial metabolite TMAO and may represent potential therapeutic targets for liver cancer.
肝癌具有较高的死亡率。慢性炎症是肝细胞癌的主要病因之一。最近的研究表明，高水平的氧化三甲胺（TMAO）可能与炎症诱导的肝癌风险增加相关。然而，TMAO促进肝癌的机制仍不清楚。在这里，我们通过用TNF-α处理Hepa1-6细胞和Huh7细胞建立了炎症诱导的肝癌模型。在TNF-α存在的情况下，TMAO协同增加了Hepa1-6细胞和Huh7细胞的增殖、迁移和侵袭。我们对炎症性肝细胞癌（HCC）的TMAO处理细胞模型进行了批量RNA测序，并使用Kaplan-Meier Plotter数据库和基因表达谱交互式分析（GEPIA）数据库评估了差异表达基因（DEGs）对临床预后的影响。使用Timer2.0对肿瘤微环境和DEGs进行单变量和多变量Cox回归分析。 、 和 的上调以及 和 的下调与人类肝癌较差的总生存期呈正相关。此外， 和 的较高表达与中性粒细胞浸润呈正相关，中性粒细胞可促进肿瘤进展。 实验表明，TMAO通过 激活ILK/AKT/mTOR信号通路，敲低 可显著降低ILK/AKT/mTOR信号通路以及Hepa1-6细胞和Huh7细胞的致瘤性。总的来说，我们的结果表明肠道微生物代谢产物TMAO和 可能代表肝癌的潜在治疗靶点。
