Aspirin Prevents Colorectal Cancer by Normalizing EGFR Expression

Haitao Li, Feng Zhu, Lisa Allyn Boardman, Lei Wang, Naomi Oi, Kangdong Liu, Xiang Li, Yang Fu, Paul John Limburg, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 from ApcMin mice, immortalized normal human colon epithelial cells (HCECs) 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 the Egfr promoter. Binding facilitates the cellular accumulation of EGFR and lowers the threshold required for pre-neoplastic cells to undergo transformation. Conclusion: Aspirin might exert its chemopreventive activity against CRC, at least partially, by normalizing EGFR expression in gastrointestinal precancerous lesions.

Original languageEnglish (US)
Pages (from-to)447-455
Number of pages9
JournalEBioMedicine
Volume2
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

Epidermal Growth Factor Receptor
Aspirin
Colorectal Neoplasms
Cyclooxygenase 2
Colon
Epithelial Cells
Immunohistochemistry
Staining and Labeling
Adenomatous Polyps
Transcription Factor AP-1
Fibroblasts
Paraffin
Carcinogenesis
Mucous Membrane
Transcription Factors
Chemical activation
Tissue

Keywords

  • Colorectal cancer
  • Cyclooxygenase-2
  • Epidermal growth factor receptor
  • Familial adenomatous polyposis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Aspirin Prevents Colorectal Cancer by Normalizing EGFR Expression. / Li, Haitao; Zhu, Feng; Boardman, Lisa Allyn; Wang, Lei; Oi, Naomi; Liu, Kangdong; Li, Xiang; Fu, Yang; Limburg, Paul John; Bode, Ann M.; Dong, Zigang.

In: EBioMedicine, Vol. 2, No. 5, 01.05.2015, p. 447-455.

Research output: Contribution to journalArticle

Li, H, Zhu, F, Boardman, LA, Wang, L, Oi, N, Liu, K, Li, X, Fu, Y, Limburg, PJ, Bode, AM & Dong, Z 2015, 'Aspirin Prevents Colorectal Cancer by Normalizing EGFR Expression', EBioMedicine, vol. 2, no. 5, pp. 447-455. https://doi.org/10.1016/j.ebiom.2015.03.019
Li, Haitao ; Zhu, Feng ; Boardman, Lisa Allyn ; Wang, Lei ; Oi, Naomi ; Liu, Kangdong ; Li, Xiang ; Fu, Yang ; Limburg, Paul John ; Bode, Ann M. ; Dong, Zigang. / Aspirin Prevents Colorectal Cancer by Normalizing EGFR Expression. In: EBioMedicine. 2015 ; Vol. 2, No. 5. pp. 447-455.
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AU - Li, Xiang

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AB - 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 from ApcMin mice, immortalized normal human colon epithelial cells (HCECs) 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 the Egfr promoter. Binding facilitates the cellular accumulation of EGFR and lowers the threshold required for pre-neoplastic cells to undergo transformation. Conclusion: Aspirin might exert its chemopreventive activity against CRC, at least partially, by normalizing EGFR expression in gastrointestinal precancerous lesions.

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