Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors

• Published in: Oncogene Vol. 24; no. 11; pp. 1882 - 1894
• Main Authors: DI VIZIO, Dolores, CITO, Letizia, TAVERNISE, Barbara, VENUTA, Salvatore, FUSCO, Alfredo, VIGLIETTO, Giuseppe, BOCCIA, Angelo, CHIEFFI, Paolo, INSABATO, Luigi, PETTINATO, Guido, LETIZIA MOTTI, Maria, SCHEPIS, Filippo, D'AMICO, Wanda, FABIANI, Fernanda
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 10.03.2005; Nature Publishing Group
• Subjects: AKT protein; Animals; Apoptosis; Biological and medical sciences; Biopsy; Breast Neoplasms; Cancer; Cell cycle; Cell growth; Cell Line, Tumor; Cell migration; Cell physiology; Cell proliferation; Cell survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Chromosome 10; Chromosomes, Human, Pair 10; Cyclin-dependent kinase; Cyclin-dependent kinase inhibitor p27; Cyclin-dependent kinases; Enzyme inhibitors; Female; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Gene expression; Genes, Tumor Suppressor; Germ cells; Germinoma - genetics; Humans; Hybridization; In Situ Hybridization; Invasiveness; Kinases; Loss of Heterozygosity; Male; Mice; Microsatellites; Molecular and cellular biology; Neurotrophin 2; Phosphatase; Phosphoric Monoester Hydrolases - genetics; Post-transcription; Proteins; PTEN Phosphohydrolase; PTEN protein; RNA, Messenger - genetics; Seminoma; Signal transduction; Teratoma; Testes; Testicular cancer; Testicular Neoplasms - genetics; Testis - cytology; Testis - embryology; Testis - pathology; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumors; Italy; Germ cell tumor; p27kip1; germ cell tumors; PTEN; Germinal cell; ITGCN; Carcinogenesis; Tumor suppressor gene; Cyclin dependent kinase inhibitor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1208368

PTEN/MMAC1/TEP1: (hereafter PTEN) is a tumor suppressor gene (located at 10q23) that is frequently mutated or deleted in sporadic human tumors. PTEN encodes a multifunctional phosphatase, which negatively regulates cell growth, migration and survival via the phosphatidylinositol 3'-kinase/AKT signalling pathway. Accordingly, Pten+/- mice develop various types of tumors including teratocarcinomas and teratomas. We have investigated PTEN expression in 60 bioptic specimens of germ cell tumors (32 seminomas, 22 embryonal carcinomas and six teratomas) and 22 intratubular germ cell neoplasias (ITGCN) adjacent to the tumors for PTEN protein and mRNA expression. In total, 10 testicular biopsies were used as controls. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of seminomas as well as from 86% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not an early event in testicular tumor development. The loss of PTEN expression occurs mainly at the RNA level as determined by in situ hybridization of cellular mRNA (17/22) but also it may involve some kind of post-transcriptional mechanisms in the remaining 25% of cases. Analysis of microsatellites D10S551, D10S541 and D10S1765 in GCTs (n=22) showed LOH at the PTEN locus at 10q23 in at least 36% of GCTs (three embryonal carcinoma, three seminoma, two teratoma); one seminoma and one embryonal (9%) carcinoma presented an inactivating mutation in the PTEN gene (2/22). Finally, we demonstrated that the phosphatidylinositol 3'-kinase/AKT pathway, which is regulated by the PTEN phosphatase, is crucial in regulating the proliferation of the NT2/D1 embryonal carcinoma cells, and that the cyclin-dependent kinase inhibitor p27(kip1) is a key downstream target of this pathway.