Bile acids‐mediated overexpression of MUC4 via FAK‐dependent c‐Jun activation in pancreatic cancer

Abstract

The majority of pancreatic cancer (PC) patients are clinically presented with obstructive jaundice with elevated levels of circulatory bilirubin and alkaline phosphatases. In the current study, we examined the implications of bile acids (BA), an important component of bile, on the pathophysiology of PC and investigated their mechanistic association in tumor-promoting functions. Integration of results from PC patient samples and autochthonous mouse models showed an elevated levels of BA (p<0.05) in serum samples compared to healthy controls. Similarly, an elevated BA levels was observed in pancreatic juice derived from PC patients (p<0.05) than non-pancreatic non-healthy (NPNH) controls, further establishing the clinical association of BA with the pathogenesis of PC. The tumor-promoting functions of BA were established by observed transcriptional upregulation of oncogenic MUC4 expression. Luciferase reporter assay revealed distal MUC4 promoter as the primary responsive site to BA. In silico analysis recognized two c-Jun binding sites at MUC4 distal promoter, which was biochemically established using ChIP assay. Interestingly, BA treatment led to an increased transcription and activation of c-Jun in a FAK-dependent manner. Additionally, BA receptor, namely FXR, which is also upregulated at transcriptional level in PC patient samples, was demonstrated as an upstream molecule in BA-mediated FAK activation, plausibly by regulating Src activation. Altogether, these results demonstrate that elevated levels of BA increase the tumorigenic potential of PC cells by inducing FXR/FAK/c-Jun axis to upregulate MUC4 expression, which is overexpressed in pancreatic tumors and is known to be associated with progression and metastasis of PC.

Acinar transformed ductal cells exhibit differential mucin expression in a tamoxifen-induced pancreatic ductal adenocarcinoma mouse model

“…After 10 to 50 weeks of tamoxifen injection, nuclear expression of FoxM1 and p-cJun was observed. This studies demonstrating potential binding sites for FoxM1 and c-Jun in the promotors of mucin genes (Joshi et al, 2016;Kong et al, 2013;Singh et al, 2007). Levels of Ncoa3, FoxM1 and p-cJun were increased in conjunction with Muc1, Muc4, Muc5Ac expression, establishing a potential link between these transcription factors and Kras G12D -regulated mucin expression in PDAC.…”

Oxysterols and Gastrointestinal Cancers Around the Clock

“…The difference in FXR expression and correlation between studies can simply be attributed to a low sample number, different groups of patients, different length of time in survival analyses, correlation with other factors etc. However, bile acids were increased in plasma and pancreatic juice in PC patients, and the mouse model confirmed the correlation between the increase in serum bile acids level with the severity of the disease (124). FXR was significantly increased in pancreatic cancer cell lines in comparison to normal pancreatic cells and FXR was found as the regulator of FAK (PTK2, protein tyrosine kinase 2)/c-Jun (JUN, Jun proto-oncogene, AP-1 transcription factor subunit) / MUC4 (mucin 4) signaling pathway (124).…”

Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis

“…Bile acids are widely involved in the pathogenesis of human malignancies, including hepatocellular carcinoma (HCC) 16 , 17 , gastric cancer 18 , esophageal cancer 19 , 20 , and pancreatic cancer 21 , 22 . Exposure to elevated fecal bile acids is associated with the occurrence of colon cancer 23 , 24 .…”