title: Aspirin Prevents Colorectal Cancer by Normalizing EGFR Expression.
abstract: BACKGROUND
  Aspirin intake reduces the risk of colorectal cancer (CRC), but the molecular underpinnings remain elusive. Epidermal growth factor receptor (EGFR), which is overexpressed in about 80% of CRC cases, is implicated in the etiology of CRC. Here, we investigated whether aspirin can prevent CRC by normalizing EGFR expression.
  
  
  METHODS
  Immunohistochemistry staining was performed on paraffin-embedded tissue sections from normal colon mucosa, adenomatous polyps from FAP patients who were classified as regular aspirin users or nonusers. The interplay between cyclooxygenase-2 (COX-2) and EGFR was studied in primary intestinal epithelial cells isolated fromApcMinmice, immortalized normal human colon epithelial cells (HCEC) as well as murine embryonic fibroblasts (MEFs).
  
  
  RESULTS
  Immunohistochemistry staining results established that EGFR overexpression is an early event in colorectal tumorigenesis, which can be greatly attenuated by regular use of aspirin. Importantly, EGFR and COX-2 were co-overexpressed and co-localized with each other in FAP patients. Further mechanistic studies revealed that COX-2 overexpression triggers the activation of the c-Jun-dependent transcription factor, activator protein-1 (AP-1), which binds to theEgfrpromoter. Binding facilitates the cellular accumulation of EGFR and lowers the threshold required for pre-neoplastic cells to undergo transformation.
  
  
  CONCLUSIONS
  Aspirin might exert its chemopreventive activity against CRC, at least partially, by normalizing EGFR expression in gastrointestinal precancerous lesions.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA ; The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, P.R. China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Boardman
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Oi
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA ; The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, P.R. China.
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA ; The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, P.R. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA ; The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA ; The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, P.R. China.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
keywords: colorectal cancer; cyclooxygenase-2; epidermal growth factor receptor; familial adenomatous polyposis