Bile acid regulates MUC2 transcription in colon cancer cells via positive EGFR/PKC/Ras/ERK/CREB, PI3K/Akt/IkappaB/NF-kappaB and p38/MSK1/CREB pathways and negative JNK/c-Jun/AP-1 pathway

Int J Oncol. 2010 Apr;36(4):941-53. doi: 10.3892/ijo_00000573.

Abstract

MUC2 is a major secretory mucin normally expressed by goblet cells of the intestine, but is aberrantly expressed in colonic neoplasia. Bile acids have been implicated in colorectal carcinogenesis and, therefore, we sought to determine the effects of bile acids on MUC2 expression and regulation in colon cancer cells. Since deoxycholic acid (DCA), a secondary bile acid, has been reported to be a potent mucin secretagogue and tumor promoter, DCA-treated HM3 colon cancer cells were analyzed using promoter-reporter assays of the 5' flanking region of the MUC2 gene. Chemical inhibitors, mutant reporter constructs and EMSA showed that DCA upregulates MUC2 transcription via multiple pathways involving activation of EGFR/PKC/Ras/Raf-1/MEK1/ERK/CREB, PI3/Akt/IkappaB/NF-kappaB and p38/MSK1/CREB while DCA induced MUC2 transcription is inhibited by JNK/c-Jun/AP-1 pathway. These results provide new insight into the complex molecular mechanisms involved in the regulation of mucin gene by bile acids in colon cancer cells that may contribute to further elucidation of colorectal carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 5' Flanking Region
  • Cell Line, Tumor
  • Colonic Neoplasms / enzymology*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Deoxycholic Acid / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • I-kappa B Proteins / antagonists & inhibitors
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Mucin-2 / genetics
  • Mucin-2 / metabolism*
  • Mutation
  • NF-kappa B / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Signal Transduction
  • Sp1 Transcription Factor / metabolism
  • Time Factors
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic
  • Transfection
  • p38 Mitogen-Activated Protein Kinases / metabolism*
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • I-kappa B Proteins
  • MUC2 protein, human
  • Mucin-2
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-jun
  • Sp1 Transcription Factor
  • Transcription Factor AP-1
  • Deoxycholic Acid
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • ras Proteins