title: The renin-angiotensin system mediates EGF receptor-vitamin d receptor cross-talk in colitis-associated colon cancer.
abstract: OBJECTIVE
  We previously showed that EGF receptor (EGFR) promotes tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model, whereas vitamin D suppresses tumorigenesis. EGFR-vitamin D receptor (VDR) interactions, however, are incompletely understood. Vitamin D inhibits the renin-angiotensin system (RAS), whereas RAS can activate EGFR. We aimed to elucidate EGFR-VDR cross-talk in colorectal carcinogenesis.
  
  
  METHODS
  To examine VDR-RAS interactions, we treated Vdr(+/+) and Vdr(-/-) mice with AOM/DSS. Effects of VDR on RAS and EGFR were examined by Western blotting, immunostaining, and real-time PCR. We also examined the effect of vitamin D3 on colonic RAS in Vdr(+/+) mice. EGFR regulation of VDR was examined in hypomorphic Egfr(Waved2) (Wa2) and Egfr(wild-type) mice. Angiotensin II (Ang II)-induced EGFR activation was studied in cell culture.
  
  
  RESULTS
  Vdr deletion significantly increased tumorigenesis, activated EGFR and β-catenin signaling, and increased colonic RAS components, including renin and angiotensin II. Dietary VD3 supplementation suppressed colonic renin. Renin was increased in human colon cancers. In studies in vitro, Ang II activated EGFR and stimulated colon cancer cell proliferation by an EGFR-mediated mechanism. Ang II also activated macrophages and colonic fibroblasts. Compared with tumors from Egfr(Waved2) mice, tumors from Egfr(wild-type) mice showed upregulated Snail1, a suppressor of VDR, and downregulated VDR.
  
  
  CONCLUSIONS
  VDR suppresses the colonic RAS cascade, limits EGFR signals, and inhibits colitis-associated tumorigenesis, whereas EGFR increases Snail1 and downregulates VDR in colonic tumors. Taken together, these results uncover a RAS-dependent mechanism mediating EGFR and VDR cross-talk in colon cancer.
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Urszula
authors.initials: U
authors.lastname: Dougherty
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Reba
authors.initials: R
authors.lastname: Mustafi
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Farhana
authors.initials: F
authors.lastname: Sadiq
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Anas
authors.initials: A
authors.lastname: Almoghrabi
authors.affiliation: Department of Radiology, University of Chicago, Chicago IL 60637.
authors.forename: Devkumar
authors.initials: D
authors.lastname: Mustafi
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Maggi
authors.initials: M
authors.lastname: Kreisheh
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Sumana
authors.initials: S
authors.lastname: Sundaramurthy
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Weicheng
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Vani J
authors.initials: VJ
authors.lastname: Konda
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Joel
authors.initials: J
authors.lastname: Pekow
authors.affiliation: Department of Medicine, University of Missouri, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201.
authors.forename: Sharad
authors.initials: S
authors.lastname: Khare
authors.affiliation: Department of Pathology, University of Chicago, Chicago IL 60637.
authors.forename: John
authors.initials: J
authors.lastname: Hart
authors.affiliation: Department of Pathology, University of Chicago, Chicago IL 60637.
authors.forename: Loren
authors.initials: L
authors.lastname: Joseph
authors.affiliation: Center for Basic MR Research, Department of Radiology, NorthShore University Health System, Evanston, IL 60201.
authors.forename: Alice
authors.initials: A
authors.lastname: Wyrwicz
authors.affiliation: Department of Radiology, University of Chicago, Chicago IL 60637.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Karczmar
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Chicago, Chicago IL 60637.
authors.forename: Marc
authors.initials: M
authors.lastname: Bissonnette
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000804:Angiotensin II; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)