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Show 131 school of medicine and health sciences Epidermal growth factor receptor (EGFR) is linked to tumor development and progression through increased cell proliferation, survival, migration, and angiogenesis. The tumor-promoting properties of EGFR are largely the result of its activation of proliferation and survival signaling pathways, but EGFR also promotes inflammation which might further facilitate tumorigenesis. EGFR induces expression of Cyclooxygenase-2 (COX-2), which helps synthesize an inflammatory lipid called PGE2. This lipid appears to be an important mediator of this inflammation. But PGE2 is also known to promote the pro-duction and/or release of EGFR ligands. In a mouse lung cancer model, we found high levels of COX-2 and EGFR along with elevated levels of amphiregulin (AR), an EGFR growth factor. These data led us to hypothesize that in this model of lung cancer, an autocrine loop develops in which EGFR promotes COX-2 expression that further activates EGFR by causing the synthesis and/or release of AR . We used two approaches to evaluate the possibility that PGE2 promotes the release of AR (Fig. 1a) or its production (Fig. 1b) in human lung tumor cells that possess activating EGFR mutations. In the first set of experiments tumor cells expressing AR on their surface were treated with PGE2 and then an ELISA was used to measure the concentration of AR present in the medium. No difference was observed in cells exposed to PGE2 versus control indicating that PGE2 doesn't cause release of AR into the medium. In the second set of experiments a vector containing a luciferase gene under the control of an AR promoter was transfected into the tumor cells which were then exposed to PGE2 . Luciferase activity in the cell lysates, an indicator of AR production, was measured using luminescence. We found high levels of luciferase activity with or without PGE2, indicating that the cells constantly produce AR. Since the cells already express COX-2, we next tested if this endogenous COX-2 promoted the produc-tion of AR. We found that a COX-2 inhibitor significantly reduced luciferase production, suggesting that the cells constitutively produce AR under the control of PGE2. Cyclooxygenase-2 and Amphiregulin in Lung Tumors with Act ivating EG FR Mutations Christopher Orlando (Matthew Topham) Department of Internal Medicine, Huntsman Cancer Institute University of Utah UNDERGRADUATE RESEARCH ABSTRACTS Christopher Orlando Matthew Topham |
