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 POSTN, LAYN and HTRA3 and downregulation of AANAT and AFM were positively related to poorer overall survival in human
liver cancer. Moreover, higher expression of POSTN and HTRA3 positively correlated with infiltration of neutrophils, which can promote
tumor progression. In vitro experiments showed
TMAO activates ILK/AKT/mTOR signaling via POSTN, and knocking down POSTN 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 POSTN may represent potential therapeutic targets for
liver cancer.