Submitted on March 21, 2007
Revised on June 26, 2007
EGFR Signaling is Required for TGF-
1-mediated COX-2 Induction in Human Bronchial Epithelial Cells
Ming Liu1, Seok-Chul Yang2, Sherven Sharma2, Jie Luo1, Xiaoyan Cui1, Katherine A Peebles1, Min Huang2, Mitsuo Sato3, Ruben D Ramirez4, Jerry W Shay5, John D Minna3, and Steven M Dubinett6*
1 Lung Cancer Research Program, UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, United States,
2 Veterans Affairs Greater Los Angeles Healthcare Center, Los Angeles, CA, USA,
3 University of Texas Southwestern Medical Center, Hamon Center for Therapeutic Oncology Research, Dallas, TX, USA,
4 University of Texas Southwestern Medical Center, Hamon Center for Therapeutic Oncology Research, Dallas, TX, USA; Dallas Veterans Affairs Medical Center, Dallas, TX, USA,
5 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA,
6 Lung Cancer Research Program, UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, United States; Veterans Affairs Greater Los Angeles Healthcare Center, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, UCLA, David Geffen School of Medicine, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: sdubinett{at}mednet.ucla.edu.
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 over-expressed 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-B1 (TGF-B1) 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-B1-mediated induction of COX-2 and corresponding prostaglandin E2 (PGE2) production. TGF-B1 and EGF induced COX-2 at the transcriptional and post-transcriptional levels. EGFR inhibition, neutralizing antibody against amphiregulin, or MEK inhibition blocked TGF-B1 mediated COX-2 induction. COX-2 induction by TGF-B1 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-B1. Thus, EGFR ligands, which are abundant in the pulmonary microenvironment of those at risk for lung cancer, potentiate and are required for COX-2 induction by TGF-B1 in HBEC. These findings emphasize the central role of EGFR signaling in COX-2 induction by TGF-B1 and suggest that inhibition of EGFR signaling should be investigated further for lung cancer prevention.
