EGFR signaling is required for TGF-β1-mediated COX-2 induction in human bronchial epithelial cells

Ming Liu, Seok Chul Yang, Sherven Sharma, Jie Luo, Xiaoyan Cui, Katherine A. Peebles, Min Huang, Mitsuo Sato, Ruben D. Ramirez, Jerry W. Shay, John D. Minna, Steven M. Dubinett

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Cyclooxygenase-2 (COX-2) is a key enzyme in the production of prostaglandins and thromboxanes from free arachidonic acid. Increasing evidence suggests that COX-2 plays a role in tumorigenesis. A variety of stimuli induce COX-2 and it is overexpressed in many tumors, including non-small cell lung cancer (NSCLC). We studied the regulation of COX-2 expression in immortalized human bronchial epithelial cells (HBECs) by transforming growth factor-β1 (TGF-β1) and epidermal growth factor (EGF) because these two growth factors are present in both the pulmonary milieu of those at risk for lung cancer as well as in the tumor microenvironment. EGF significantly enhanced TGF-β1-mediated induction of COX-2 and corresponding prostaglandin E2 (PGE2) production. TGF-β1 and EGF induced COX-2 at the transcriptional and post-transcriptional levels. EGF receptor (EGFR) inhibition, neutralizing antibody against amphiregulin, or mitogen-activated protein kinase kinase (MEK) inhibition blocked TGF-β1-mediated COX-2 induction. COX-2 induction by TGF-β1 depended upon Smad3 signaling and required the activity of EGFR or its downstream mediators. Autocrine amphiregulin signaling maintains EGFR in a constitutively active state in HBECs, allowing for COX-2 induction by TGF-β1. Thus, EGFR ligands, which are abundant in the pulmonary microenvironment of those at riskfor lung cancer, potentiate and are required for COX-2 induction by TGF-β1 in HBEC. These findings emphasize the central role of EGFR signaling in COX-2 induction by TGF-β1 and suggest that inhibition of EGFR signaling should be investigated further for lung cancer prevention.

Original languageEnglish (US)
Pages (from-to)578-588
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume37
Issue number5
DOIs
StatePublished - Nov 2007

Keywords

  • Cyclooxygenase-2
  • Epidermal growth factor receptor
  • Lung cancer
  • Smad3
  • Transforming growth factor-β1

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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    Liu, M., Yang, S. C., Sharma, S., Luo, J., Cui, X., Peebles, K. A., Huang, M., Sato, M., Ramirez, R. D., Shay, J. W., Minna, J. D., & Dubinett, S. M. (2007). EGFR signaling is required for TGF-β1-mediated COX-2 induction in human bronchial epithelial cells. American journal of respiratory cell and molecular biology, 37(5), 578-588. https://doi.org/10.1165/rcmb.2007-0100OC