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

Suhasini Joshi, Eric Cruz, Satyanarayana Rachagani, Sushovan Guha, Randall E. Brand, Moorthy Palanimuthu Ponnusamy, Sushil Kumar, Surinder Kumar Batra

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1063-1077
Number of pages15
JournalMolecular Oncology
Volume10
Issue number7
DOIs
StatePublished - Aug 1 2016

Fingerprint

Bile Acids and Salts
Pancreatic Neoplasms
Up-Regulation
Pancreatic Juice
Neoplasms
Obstructive Jaundice
Luciferases
Bilirubin
Bile
Computer Simulation
Transcriptional Activation
Alkaline Phosphatase
Binding Sites
Neoplasm Metastasis

Keywords

  • Bile acids
  • FAK
  • FXR
  • MUC4
  • Pancreatic cancer
  • c-Jun

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cancer Research

Cite this

Bile acids-mediated overexpression of MUC4 via FAK-dependent c-Jun activation in pancreatic cancer. / Joshi, Suhasini; Cruz, Eric; Rachagani, Satyanarayana; Guha, Sushovan; Brand, Randall E.; Palanimuthu Ponnusamy, Moorthy; Kumar, Sushil; Batra, Surinder Kumar.

In: Molecular Oncology, Vol. 10, No. 7, 01.08.2016, p. 1063-1077.

Research output: Contribution to journalArticle

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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.",
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