Bile accelerates carcinogenic processes in pancreatic ductal adenocarcinoma cells through the overexpression of MUC4

Abstract

Pancreatic cancer (PC) is one of the leading causes of mortality rate globally and is usually associated with obstructive jaundice (OJ). Up to date, there is no clear consensus on whether biliary decompression should be performed prior to surgery and how high levels of serum bile affects the outcome of PC. Therefore, our study aims were to characterise the effect of bile acids (BAs) on carcinogenic processes using pancreatic ductal adenocarcinoma (PDAC) cell lines and to investigate the underlying mechanisms. Liquid chromatography-mass spectrometry was used to determine the serum concentrations of BAs. The effects of BAs on tumour progression were investigated using different assays. Mucin expressions were studied in normal and PDAC cell lines and in human samples at gene and protein levels and results were validated with gene silencing. The levels of BAs were significantly higher in the PDAC + OJ group compared to the healthy control. Treating PDAC cells with different BAs or with human serum obtained from PDAC + OJ patients enhanced the rate of proliferation, migration, adhesion, colony forming, and the expression of MUC4. In PDAC + OJ patients, MUC4 expression was higher and the 4-year survival rate was lower compare to PDAC patients. Silencing of MUC4 decreased BAs-induced carcinogenic processes in PDAC cells. Our results show that BAs promote carcinogenic process in PDAC cells, in which the increased expression of MUC4 plays an important role. Based on these results, we assume that in PC patients, where the disease is associated with OJ, the early treatment of biliary obstruction improves life expectancy.

Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer

“…3a–c ). We also tested other microbiota-modulated metabolites that have implications in different gastrointestinal cancers, such as the secondary bile acid deoxycholic acid (DCA) and the primary bile acid glycocholic acid (GCA) 18 , 19 . In addition, we chose to test two other metabolites that were increased in R patients or R-microbiota-colonized gnotobiotic mice—namely, the indole derivate indole-3-propionic acid (IPA) and hippuric acid—in combination with FIRINOX.…”

The bacterial metabolite, lithocholic acid, has antineoplastic effects in pancreatic adenocarcinoma

“…Conjugated bile acid levels (glycocholic acid detected in most cases) are elevated in the plasma and serum samples from PDAC patients compared to controls [58, [95][96][97][98][99]. The levels of unconjugated bile acids in the plasma of PDAC patients are reduced [98].…”

Mechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis: a comprehensive and systematic review

“… 122 Likewise, in both PDAC cell lines and human samples, it was found that bile accelerates carcinogenesis through the overexpression of MUC4. 123 In addition to their contribution to pancreatic carcinogenesis via insulin resistance [or elevated insulin-like growth factor 1 (IGF-1) signaling], hyperinsulinemia, and the disruption of the GM in obesity and DM, BAs also elevate the risk of PC via gallstones, pancreatobiliary maljunction, and chronic pancreatitis. 117 , 124 Moreover, BAs can have much more direct and local effects on carcinogenesis.…”