Association of ADAM12 with head and neck cancer development

Abstract

Abstract|Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide. Despite aggressive treatment, fewer than half of the thirty-seven thousand HNSCC patients each year in the United States will survive five years beyond diagnosis. Although 95% of HNSCC express the epidermal growth factor receptor (EGFR), the use of EGFR inhibitors over the past decade has had little impact on patient outcomes. Given the importance of EGFR and its binding partner HER2 in HNSCC, EGFR-regulated gene expression was investigated. One EGFR-regulated transcript, A Disintegrin and Metalloproteinase 12 (ADAM12), is over-expressed in 90% of HNSCCs and correlates with tumor progression. ADAM12 and EGFR family members form a positive feedback loop in human HNSCC cells. Accordingly, we proposed that targeting of ADAM12 may be an effective strategy for HNSCC treatment, especially when used to improve the efficacy of EGFR inhibition. Analysis of published HNSCC microarray data revealed 13-fold and 20-fold increases in ADAM12 transcripts in human head and neck dysplasias and HNSCC, respectively. ADAM12 transcripts were significantly increased in HNSCC regardless of Human Papilloma Virus status. EGFR increased 1.65-fold in cancer samples, and did not significantly increase in dysplasia. To investigate head and neck cancer in a mouse model, mice were treated for 16 weeks with the mutagen 4-nitroquinoline 1-oxide (4-NQO). An average of 4.8 ± 0.5 grossly observable pathologies were identified in the mice at 22 weeks. Histopathological characterization revealed 2.8 ± 0.3 dysplasias, 0.35 ± 0.1 papillomas, and 0.8 ± 0.2 SCC per mouse tongue. Surprisingly, some SCC were not grossly observable while many of the gross lesions were identified as dysplasias. In addition, ADAM12, EGFR and phospho-EGFR were detected using immunofluorescence in both vehicle and 4-NQO treated tongues. These data suggest that the 4-NQO regimen may be a useful model for analysis of the role of ADAM12 and EGFR in oral carcinogenesis.