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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.

SUBMITTER: Gal E

PROVIDER: S-EPMC7744548 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Background Mucin 4 (MUC4) overexpression promotes tumorigenesis and increases the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). To date, no study has reported the association between radiomics and MUC4 expression in PDAC. Thus, we aimed to explore the utility of radiomics based on multi-sequence magnetic resonance imaging (MRI) to predict the status of MUC4 expression in PDAC preoperatively. Methods This retrospective study included 52 patients with PDAC who underwent MRI. The patients were divided into two groups based on MUC4 expression status. Two feature sets were extracted from the arterial and portal phases (PPs) of dynamic contrast-enhanced MRI (DCE-MRI). Univariate analysis, minimum redundancy maximum relevance (MRMR), and principal component analysis (PCA) were performed for the feature selection of each dataset, and features with a cumulative variance of 90% were selected to develop radiomics models. Clinical characteristics were gathered to develop a clinical model. The selected radiomics features and clinical characteristics were modeled by multivariable logistic regression. The combined model integrated radiomics features from different selected data sets and clinical characteristics. The classification metrics were applied to assess the discriminatory power of the models. Results There were 22 PDACs with a high expression of MUC4 and 30 PDACs with a low expression of MUC4. The area under the receiver operating characteristic (ROC) curve (AUC) values of the arterial phase (AP) model, the PP model, and the combined model were 0.732 (0.591–0.872), 0.709 (0.569–0.849), and 0.861 (0.760–0.961), respectively. The AUC of the clinical model was 0.666 (0.600–0.682). The combined model that was constructed outperformed the AP, the PP, and the clinical models (P<0.05, although no statistical significance was observed in the combined model vs. AP model). Conclusions Radiomics models based on multi-sequence MRI have the potential to predict MUC4 expression levels in PDAC.

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

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