Integrated Analysis Reveals the Gut Microbial Metabolite TMAO Promotes Inflammatory Hepatocellular Carcinoma by Upregulating POSTN

Abstract

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.

Analysis of Immune-Related and Angiogenesis-Related Genes in Hepatocellular Carcinoma: Implications for Prognosis and Drug Sensitivity

“…Previous studies have reported a positive correlation between the upregulation of POSTN and poor overall survival in human hepatocellular carcinoma (HCC) 14 . Additionally, high expression levels of POSTN have been found to positively correlate with neutrophil in ltration, thereby promoting tumor progression.…”

Molecular mechanisms of metabolic disease-associated hepatic inflammation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

“…Dysbiosis of gut microbiota and increased intestinal permeability result in NAFLD progression by increasing the transportation of gut-microbiotaderived components and metabolites into the liver [62]. For example, gut-microbiota-derived metabolite trimethylamine N-oxide (TMAO) from dietary choline, carnitine, and L-carnitine can aggravate hepatic steatosis in NAFLD by regulating BA metabolism through the regulation of farnesoid X receptor (FXR) signaling pathway [63]. In vitro treatment of TMAO together with pro-inflammatory cytokine TNF-α can increase the proliferation (detected by the cell-counting Kit-8 assay), migration (detected by the wound healing assay and the transwell assay), and invasion [detected by the expression levels of periostin, integrin-linked kinase (ILK)/RAC-α serine/threonine-protein kinase (AKT1), and the mammalian target of rapamycin (mTOR)] of mouse liver cancer cell line Hepa1-6 cells and human liver cancer cell line Huh7 cells [64].…”

Oxidative stress bridges the gut microbiota and the occurrence of frailty syndrome

“…However, it inhibits the production of endothelial nitric oxide (NO) synthase and NO[ 41 ]. It has also been reported that TMAO can promote inflammatory hepatocellular carcinoma by inducing ROS and activating ILK/AKT/mammalian target of rapamycin (mTOR) signaling via POSTN[ 42 ]. Our previous studies showed that administration of TMAO produced a novel model of frailty in mice[ 43 ].…”