Expression and Function of the Vitamin D Receptor in Malignant Germ Cell Tumour of the Testis

Testicular germ cell tumours (TGCTs) are the most common malignancy in young men aged 18-35 years. They are clinically and histologically subdivided into seminomas and non-seminomas. 1,25-Dihydroxyvitamin D (1,25(OH) 2 D 3 ) is the active form of vitamin D and exerts its actions via a specific intracellular vitamin D receptor (VDR). Several investigations in the recent years have revealed, in addition to a physiological occurrence of the VDR in various tissues, VDR expression in different human malignancies. Furthermore, 1,25(OH) 2 D 3 plays an important role in the regulation of cell proliferation and differentiation. In different normal and malignant cell types, antiproliferative and pro-differentiating effects of 1,25(OH) 2 D 3 are described. We investigated whether TGCT express the VDR, wether differences exist between the histological subtypes and if vitamin D has a function on the proliferation of tumour cells. Furthermore, we investigated the potential function of the vitamin D-regulated genes nuclear receptor co-repressor 1(NCOR1), nuclear receptor co-repressor 2 (NCOR2), thyroid receptor interacting protein 15 (TRIP15), Growth Arrest and DNA Damage (GADD45), MAP kinase-activated protein kinase 2 (MAPKAPK2), Cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) and Cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1) in the pathogenesis of TGCT. We demonstrate, for the first time, that primary TGCT as well as TGCT cell lines, express VDR mRNA and protein. Vitamin D and VDR may play a role in the pathogenesis of TGCTs. Furthermore, vitamin D inhibits proliferation of TGCT cell-lines, potentially via an increase in expression of GADD45. Our data suggest that vitamin D could play a role in antitumour therapy. Testicular germ cell tumours (TGCTs) represent the most common malignant tumours in men aged 18 to 35 years and comprise 98% of all testicular malignancies. The incidence is constantly increasing in Europe as well as in the U.S.A., having doubled over the last 40 years (1). Histologically, TGCTs are divided into two main groups, seminomas and nonseminomas, the nonseminomas being subdivided into embryonal carcinomas, yolk sac tumours, chorioniccarcinomas and teratomas (2). All invasive testicular germ cell tumours arise from intratubular germ cell neoplasia, unclassified type, (IGCNU) which represent the precursor lesions of invasive TGCT (3).