Bile acids promote diethylnitrosamine-induced hepatocellular carcinoma via increased inflammatory signaling

Abstract

Hepatocellular carcinoma (HCC) is the most common hepatic malignancy and the third leading cause of cancer related deaths. Previous studies have implicated bile acids in pathogenesis of HCC, but the mechanisms are not known. We investigated the mechanisms of HCC tumor promotion by bile acids the diethylnitrosamine (DEN)-initiation-cholic acid (CA)-induced tumor promotion protocol in mice. The data show that 0.2% CA treatment resulted in threefold increase in number and size of DEN-induced liver tumors. All tumors observed in DEN-treated mice were well-differentiated HCCs. The HCCs observed in DEN-treated CA-fed mice exhibited extensive CD3-, CD20-, and CD45-positive inflammatory cell aggregates. Microarray-based global gene expression studies combined with Ingenuity Pathway Analysis revealed significant activation of NF-κB and Nanog in the DEN-treated 0.2% CA-fed livers. Further studies showed significantly higher TNF-α and IL-1β mRNA, a marked increase in total and phosphorylated-p65 and phosphorylated IκBα (degradation form) in livers of DEN-treated 0.2% CA-fed mice. Treatment of primary mouse hepatocytes with various bile acids showed significant induction of stemness genes including Nanog, KLF4, Sox2, and Oct4. Quantification of total and 20 specific bile acids in liver, and serum revealed a tumor-associated bile acid signature. Finally, quantification of total serum bile acids in normal, cirrhotic, and HCC human samples revealed increased bile acids in serum of cirrhotic and HCC patients. Taken together, these data indicate that bile acids are mechanistically involved pathogenesis of HCC and may promote HCC formation via activation of inflammatory signaling.

Microbiome and bile acid profiles in duodenal aspirates from patients with liver cirrhosis: The Microbiome, Microbial Markers and Liver Disease Study

“…However, recent advances in our understanding of gut microbes, microbial products, and bile acids have provided insight into how imbalances in the gut–liver axis influence the progression from cirrhosis to HCC . Lipopolysaccharide (also known as endotoxin, a potent immunogenic component of certain bacterial cell membranes) can promote hepatocyte damage and transformation by activating immune cells, inducing cytokine secretion, and inducing reactive oxygen species . Furthermore, one of the major roles of the gut microbiome is to metabolize primary bile acids into secondary bile acids to be recirculated as part of the enterohepatic circulation .…”

“…Furthermore, one of the major roles of the gut microbiome is to metabolize primary bile acids into secondary bile acids to be recirculated as part of the enterohepatic circulation . In cirrhosis, inefficiency in capturing and secreting bile acids results in bile acid accumulation in the liver where they can act as carcinogens . Therefore, the gut microbiota and bile acid analysis can provide the basis for potentially novel biomarkers.…”

The nuclear translocation of transketolase inhibits the farnesoid receptor expression by promoting the binding of HDAC3 to FXR promoter in hepatocellular carcinoma cell lines

“…Studies have indicated deoxycholic acid DCA can cause DNA damage, activation of hepatic stellate cells and the secretion of inflammatory tumor promoting factor. Intrahepatic cholestasis induces excessive fat accumulation, which could cause hepatocyte damage and inflammation, then promotes HCC 24 . Lithocholic acid (LCA) can stimulate the malignant proliferation of colon and breast cancer cells 25,26 .…”

Prognostic value of a metastasis-related gene signature in hepatocellular carcinoma

“…Bile acids serve as signaling molecules in the liver that regulate lipid and glucose homeostasis [44]. They play an important role in the sustentation of inflammation, and thus the development and promotion of HCC [45,46]. In cancer cells, 95% of fatty acids come from de novo synthesis [47].…”