title: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, United States.
authors.forename: Suhasini
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Cruz
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, United States.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Rachagani
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, UT Health-UT Health Science Center and Medical School at Houston, Houston, TX, United States.
authors.forename: Sushovan
authors.initials: S
authors.lastname: Guha
authors.affiliation: Division of Gastroenterology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Randall E
authors.initials: RE
authors.lastname: Brand
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, United States; Buffett Cancer Center, Omaha, NE 68198, United States; Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE 68198, United States.
authors.forename: Moorthy P
authors.initials: MP
authors.lastname: Ponnusamy
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, United States. Electronic address: skumar@unmc.edu.
authors.forename: Sushil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, United States; Buffett Cancer Center, Omaha, NE 68198, United States; Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE 68198, United States; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: sbatra@unmc.edu.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
mesh_terms: D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008822:Mice, Transgenic; D055264:Mucin-4 / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D051416:Focal Adhesion Protein-Tyrosine Kinases; D055264:Mucin-4; D016755:Proto-Oncogene Proteins c-jun; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated
keywords: Bile acids; FAK; FXR; MUC4; Pancreatic cancer; c-Jun