Specific Deletion of p16 with Retention of p19 Enhances the Development of Invasive Oral Squamous Cell Carcinoma.

The cyclin-dependent kinase inhibitor 2A (CDKN2A)/alternate reading frame (ARF) locus consists of two overlapping tumor suppressor genes, p16 and p14 (p19 in mice), encoding two unrelated proteins in alternative reading frames. Previous reports suggest that p16 and p14 alterations independently exhibit differential roles, and p16 is more closely associated with a poor prognosis in oral cancer. However, the role of p16-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-specific loss with retention of the p19 gene (p16). 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 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-specific loss with retention of p19 in oral squamous cell carcinogenesis, and ΔNp63 may be a potential target for OSCC.