Lack of p19^INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

Abstract

p19^INK4d, a member of the INK4 family of cyclin-dependent kinase inhibitors, negatively regulates the proto-oncogenic cyclin D/CDK4(6) complexes whose ability to phosphorylate the retinoblastoma tumour suppressor (RB) promotes G1/S transition. In contrast to the related p16^INK4a tumour suppressor, expression patterns of 19^INK4d in human tissues and tumours remain unknown. As the RB pathway is commonly targeted in cancer, and mouse models suggest a role for p19^INK4d in spermatogenesis, we examined the abundance and localization of p19^INK4d in the human testis, both during normal development and at various stages of germ-cell tumour pathogenesis. Our data show that the p19^INK4d protein is abundant in spermatocytes of normal human adult testes, whereas virtually no p19^INK4d is detectable in testicular cancer, including the preinvasive carcinoma in situ stage. Together with the lack of p19^INK4d in human foetal germ cells, these results support the concept of foetal origin of the testicular germ-cell tumours, and help better understand the emerging role of the RB pathway in spermatogenesis and tumorigenesis in the human testis.