Specific Deletion of p16INK4a with Retention of p19ARF Enhances the Development of Invasive Oral Squamous Cell Carcinoma

Abstract

The cyclin-dependent kinase inhibitor 2A (CDKN2A)/alternate reading frame (ARF) locus consists of two overlapping tumor suppressor genes, p16^INK4a and p14^ARF (p19^ARF in mice), encoding two unrelated proteins in alternative reading frames. Previous reports suggest that p16^INK4a and p14^ARF alterations independently exhibit differential roles, and p16^INK4a is more closely associated with a poor prognosis in oral cancer. However, the role of p16^INK4a-specific loss in oral squamous cell carcinogenesis remains unclear. The authors assessed chemical carcinogen 4-nitroquinoline 1-oxide (4NQO)-induced multistep oral squamous cell carcinogenesis in mice carrying p16^INK4a-specific loss with retention of the p19^ARF gene (p16^INK4a-/-). 4NQO-treated p16^-/- mice exhibited a higher incidence and multiplicity of oral squamous cell carcinoma (OSCC) development relative to 4NQO-treated wild-type mice. 4NQO-treated p16^INK4a-/- OSCC cells exhibited higher proliferation and up-regulation of Arf, transcription factor E2f1, tumor protein p63 (tp63), and oncogenic ΔNp63, an isoform p63, compared with observations in 4NQO-treated wild-type OSCC cells. Furthermore, the overexpression of oncogenic ΔNp63 was associated with human OSCC. In conclusion, these results in mice indicate the biological significance of p16^INK4a-specific loss with retention of p19^ARF in oral squamous cell carcinogenesis, and ΔNp63 may be a potential target for OSCC.