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The renin-angiotensin system mediates epidermal growth factor receptor-vitamin D receptor cross-talk in colitis-associated colon cancer.
MedLine Citation:
PMID:  25212605     Owner:  NLM     Status:  Publisher    
Purpose: We previously showed that epidermal growth factor receptor (EGFR) promotes tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model, whereas vitamin D (VD) suppresses tumorigenesis. EGFR-vitamin D receptor (VDR) interactions, however, are incompletely understood. VD 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 Westerns, 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 ((Wa2)) and Egfr(wildtype) mice. 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 to tumors from Egfr(Waved2) mice, tumors from Egfr(wildtype) mice showed up-regulated Snail1, a suppressor of VDR, and down-regulated VDR. Conclusions: VDR suppresses the colonic RAS cascade, limits EGFR signals and inhibits colitis-associated tumorigenesis, whereas EGFR increases Snail1 and down-regulates VDR in colonic tumors. Taken together, these results uncover a RAS-dependent mechanism mediating EGFR and VDR cross-talk in colon cancer.
Urszula Dougherty; Reba Mustafi; Farhana Sadiq; Anas Almoghrabi; Devkumar Mustafi; Maggi Kreisheh; Sumana Sundaramurthy; Weicheng Liu; Vani J Konda; Joel Pekow; Sharad Khare; John Hart; Loren Joseph; Alice Wyrwicz; Gregory S Karczmar; Yan Chun Li; Marc Bissonnette
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-9-11
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  -     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2014 Sep 
Date Detail:
Created Date:  2014-9-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014, American Association for Cancer Research.
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