Your browser doesn't support javascript.
loading
The renin-angiotensin system mediates EGF receptor-vitamin d receptor cross-talk in colitis-associated colon cancer.
Dougherty, Urszula; Mustafi, Reba; Sadiq, Farhana; Almoghrabi, Anas; Mustafi, Devkumar; Kreisheh, Maggi; Sundaramurthy, Sumana; Liu, Weicheng; Konda, Vani J; Pekow, Joel; Khare, Sharad; Hart, John; Joseph, Loren; Wyrwicz, Alice; Karczmar, Gregory S; Li, Yan Chun; Bissonnette, Marc.
Afiliación
  • Dougherty U; Department of Medicine, University of Chicago, Chicago IL 60637.
  • Mustafi R; Department of Medicine, University of Chicago, Chicago IL 60637.
  • Sadiq F; Department of Medicine, University of Chicago, Chicago IL 60637.
  • Almoghrabi A; Department of Medicine, University of Chicago, Chicago IL 60637.
  • Mustafi D; Department of Radiology, University of Chicago, Chicago IL 60637.
  • Kreisheh M; Department of Medicine, University of Chicago, Chicago IL 60637.
  • Sundaramurthy S; Department of Medicine, University of Chicago, Chicago IL 60637.
  • Liu W; Department of Medicine, University of Chicago, Chicago IL 60637.
  • Konda VJ; Department of Medicine, University of Chicago, Chicago IL 60637.
  • Pekow J; Department of Medicine, University of Chicago, Chicago IL 60637.
  • Khare S; Department of Medicine, University of Missouri, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201.
  • Hart J; Department of Pathology, University of Chicago, Chicago IL 60637.
  • Joseph L; Department of Pathology, University of Chicago, Chicago IL 60637.
  • Wyrwicz A; Center for Basic MR Research, Department of Radiology, NorthShore University Health System, Evanston, IL 60201.
  • Karczmar GS; Department of Radiology, University of Chicago, Chicago IL 60637.
  • Li YC; Department of Medicine, University of Chicago, Chicago IL 60637.
  • Bissonnette M; Department of Medicine, University of Chicago, Chicago IL 60637.
Clin Cancer Res ; 20(22): 5848-5859, 2014 Nov 15.
Article en En | MEDLINE | ID: mdl-25212605
ABSTRACT

PURPOSE:

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. EXPERIMENTAL

DESIGN:

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 ß-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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Renina-Angiotensina / Receptores de Calcitriol / Colitis / Neoplasias del Colon / Receptor Cross-Talk / Receptores ErbB Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2014 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Renina-Angiotensina / Receptores de Calcitriol / Colitis / Neoplasias del Colon / Receptor Cross-Talk / Receptores ErbB Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2014 Tipo del documento: Article