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.
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.
Lee
Hwa Young
HY
Department of Gastroenterology, College of Medicine, Kangnam CHA Hospital, CHA University, Seoul, 650-9, Korea.
Crawley
Suzanne
S
Hokari
Ryota
R
Kwon
Sungwon
S
Kim
Young S
YS
D024506:5' Flanking Region; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D003840:Deoxycholic Acid; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020672:I-kappa B Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D055262:Mucin-2; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D016755:Proto-Oncogene Proteins c-jun; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins; C115163:CREB1 protein, human; C524625:MUC2 protein, human; C512478:EGFR protein, human; C116919:mitogen and stress-activated protein kinase 1