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

Dolores Di Vizio, Letizia Cito, Angelo Boccia, Paolo Chieffi, Luigi Insabato, Guido Pettinato, Maria Letizia Motti, Filippo Schepis, Wanda D'Amico, Fernanda Fabiani, Barbara Tavernise, Salvatore Venuta, Alfredo Fusco, Giuseppe Viglietto

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

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 posttranscriptional 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 p27kip1 is a key downstream target of this pathway.

Original languageEnglish
Pages (from-to)1882-1894
Number of pages13
JournalOncogene
Volume24
Issue number11
DOIs
Publication statusPublished - Mar 10 2005

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Germ Cell and Embryonal Neoplasms
Embryonal Carcinoma
Tumor Suppressor Genes
Seminoma
Germ Cells
Teratoma
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinase
Neoplasms
Teratocarcinoma
Embryonal Carcinoma Stem Cells
Messenger RNA
Cyclin-Dependent Kinases
Testicular Neoplasms
Phosphoric Monoester Hydrolases
Microsatellite Repeats
Cell Movement
In Situ Hybridization
Testis
Cell Survival

Keywords

  • Germ cell tumors
  • ITGCN
  • p27
  • PTEN

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Di Vizio, D., Cito, L., Boccia, A., Chieffi, P., Insabato, L., Pettinato, G., ... Viglietto, G. (2005). Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. Oncogene, 24(11), 1882-1894. https://doi.org/10.1038/sj.onc.1208368

Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. / Di Vizio, Dolores; Cito, Letizia; Boccia, Angelo; Chieffi, Paolo; Insabato, Luigi; Pettinato, Guido; Motti, Maria Letizia; Schepis, Filippo; D'Amico, Wanda; Fabiani, Fernanda; Tavernise, Barbara; Venuta, Salvatore; Fusco, Alfredo; Viglietto, Giuseppe.

In: Oncogene, Vol. 24, No. 11, 10.03.2005, p. 1882-1894.

Research output: Contribution to journalArticle

Di Vizio, D, Cito, L, Boccia, A, Chieffi, P, Insabato, L, Pettinato, G, Motti, ML, Schepis, F, D'Amico, W, Fabiani, F, Tavernise, B, Venuta, S, Fusco, A & Viglietto, G 2005, 'Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors', Oncogene, vol. 24, no. 11, pp. 1882-1894. https://doi.org/10.1038/sj.onc.1208368
Di Vizio, Dolores ; Cito, Letizia ; Boccia, Angelo ; Chieffi, Paolo ; Insabato, Luigi ; Pettinato, Guido ; Motti, Maria Letizia ; Schepis, Filippo ; D'Amico, Wanda ; Fabiani, Fernanda ; Tavernise, Barbara ; Venuta, Salvatore ; Fusco, Alfredo ; Viglietto, Giuseppe. / Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. In: Oncogene. 2005 ; Vol. 24, No. 11. pp. 1882-1894.
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abstract = "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 posttranscriptional 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 p27kip1 is a key downstream target of this pathway.",
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AU - Cito, Letizia

AU - Boccia, Angelo

AU - Chieffi, Paolo

AU - Insabato, Luigi

AU - Pettinato, Guido

AU - Motti, Maria Letizia

AU - Schepis, Filippo

AU - D'Amico, Wanda

AU - Fabiani, Fernanda

AU - Tavernise, Barbara

AU - Venuta, Salvatore

AU - Fusco, Alfredo

AU - Viglietto, Giuseppe

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