Elevation of the epidermal growth factor receptor and dependent signaling in human papillomavirus-infected laryngeal papillomas

Laryngeal papillomas are benign tumors caused by human papillomaviruses typ es 6 and 11. This study addressed alterations in levels of signal transduct ion from the epidermal growth factor receptor (EGFR) in papillomas and cult ured papilloma cells compared to normal tissue and cells. Mitogen-activated protein kinase (MAPK) was activated to a greater extent, phosphotyrosine w as more abundant. and EGFR was overexpressed in laryngeal papillomas compar ed to normal laryngeal epithelium by Western blot analysis. The EGFR was 3 times more abundant in cultured papilloma cells than in normal laryngeal ce lls by Scatchard analysis and Western blot, without gene amplification or a n increase in steady-state levels of mRNA. Following stimulation with EGF, a significant portion of the EGFR was recycled to the surface in papilloma cells, whereas in normal cells, it was not. Tyrosine kinase activity and ac tivation of MAPK was more responsive to epidermal growth factor stimulation in papilloma cells than in uninfected primary laryngeal cells. PD153035, a specific inhibitor of the EGFR, and an EGFR-specific antibody that blocks ligand binding completely abrogated basal MAPK activation by endogenous lig ands in laryngeal papilloma cells. These results demonstrated that infectio n of laryngeal epithelium by low-risk human papillomaviruses elevates the E GFR by posttranslational mechanisms, increasing its responsiveness to ligan d-mediated activation. They also showed that MAPK activation in laryngeal p apillomas depends upon ligand-mediated EGFR stimulation.