Specific Deletion of p16 INK4a with Retention of p19 ARF 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 ^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.
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