Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small-cell lung carcinomas

Nicola Amodio, Marianna Scrima, Lucia Palaia, Ali Naeem Salman, Alfina Quintiero, Renato Franco, Gerardo Botti, Pino Pirozzi, Gaetano Rocco, Nicla De Rosa, Giuseppe Viglietto

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Abstract

Loss of the PTEN tumor suppressor gene occurs frequently in non-small-cell lung carcinoma (NSCLC), although neither genetic alterations nor epigenetic silencing are significant predictors of PTEN protein levels. Since recent reports implicated neural precursor cell expressed, developmentally down-regulated 4-1 (NEDD4-1) as the E3 ubiquitin ligase that regulates PTEN stability, we investigated the role of NEDD4-1 in the regulation of PTEN expression in cases of NSCLC. Our findings indicate that NEDD4-1 plays a critical role in the development of NSCLC and provides novel insight on the mechanisms that contribute to inactivate PTEN in lung cancer. Immunohistochemical analysis on tissue microarrays containing 103 NSCLC resections revealed NEDD4-1 overexpression in 80% of tumors, which correlated with the loss of PTEN protein (n = 98; P <0.001). Accordingly, adoptive NEDD4-1 expression in NSCLC cells decreased PTEN protein stability, whereas knock-down of NEDD4-1 expression decreased PTEN ubiquitylation and increased PTEN protein levels. In 25% of cases, NEDD4-1 overexpression was due to gene amplification at 15q21. In addition, manipulation of NEDD4-1 expression in different lung cell systems demonstrated that suppression of NEDD4-1 expression significantly reduced proliferation of NSCLC cells in vitro and tumor growth in vivo, whereas NEDD4-1 overexpression facilitated anchorage-dependent and independent growth in vitro of nontransformed lung epithelial cells that lack pRB and TP53 (BEAS-2B). NEDD4-1 overexpression also augmented the tumorigenicity of lung cancer cells that have an intact PTEN gene (NCI-H460 cells).

Original languageEnglish
Pages (from-to)2622-2634
Number of pages13
JournalAmerican Journal of Pathology
Volume177
Issue number5
DOIs
Publication statusPublished - Nov 2010

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Ubiquitin-Protein Ligases
Non-Small Cell Lung Carcinoma
PTEN Phosphohydrolase
Lung Neoplasms
Tissue Array Analysis
Lung
Gene Amplification
Protein Stability
Ubiquitination
Growth
Tumor Suppressor Genes
Epigenomics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Amodio, N., Scrima, M., Palaia, L., Salman, A. N., Quintiero, A., Franco, R., ... Viglietto, G. (2010). Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small-cell lung carcinomas. American Journal of Pathology, 177(5), 2622-2634. https://doi.org/10.2353/ajpath.2010.091075

Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small-cell lung carcinomas. / Amodio, Nicola; Scrima, Marianna; Palaia, Lucia; Salman, Ali Naeem; Quintiero, Alfina; Franco, Renato; Botti, Gerardo; Pirozzi, Pino; Rocco, Gaetano; De Rosa, Nicla; Viglietto, Giuseppe.

In: American Journal of Pathology, Vol. 177, No. 5, 11.2010, p. 2622-2634.

Research output: Contribution to journalArticle

Amodio, N, Scrima, M, Palaia, L, Salman, AN, Quintiero, A, Franco, R, Botti, G, Pirozzi, P, Rocco, G, De Rosa, N & Viglietto, G 2010, 'Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small-cell lung carcinomas', American Journal of Pathology, vol. 177, no. 5, pp. 2622-2634. https://doi.org/10.2353/ajpath.2010.091075
Amodio, Nicola ; Scrima, Marianna ; Palaia, Lucia ; Salman, Ali Naeem ; Quintiero, Alfina ; Franco, Renato ; Botti, Gerardo ; Pirozzi, Pino ; Rocco, Gaetano ; De Rosa, Nicla ; Viglietto, Giuseppe. / Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small-cell lung carcinomas. In: American Journal of Pathology. 2010 ; Vol. 177, No. 5. pp. 2622-2634.
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abstract = "Loss of the PTEN tumor suppressor gene occurs frequently in non-small-cell lung carcinoma (NSCLC), although neither genetic alterations nor epigenetic silencing are significant predictors of PTEN protein levels. Since recent reports implicated neural precursor cell expressed, developmentally down-regulated 4-1 (NEDD4-1) as the E3 ubiquitin ligase that regulates PTEN stability, we investigated the role of NEDD4-1 in the regulation of PTEN expression in cases of NSCLC. Our findings indicate that NEDD4-1 plays a critical role in the development of NSCLC and provides novel insight on the mechanisms that contribute to inactivate PTEN in lung cancer. Immunohistochemical analysis on tissue microarrays containing 103 NSCLC resections revealed NEDD4-1 overexpression in 80{\%} of tumors, which correlated with the loss of PTEN protein (n = 98; P <0.001). Accordingly, adoptive NEDD4-1 expression in NSCLC cells decreased PTEN protein stability, whereas knock-down of NEDD4-1 expression decreased PTEN ubiquitylation and increased PTEN protein levels. In 25{\%} of cases, NEDD4-1 overexpression was due to gene amplification at 15q21. In addition, manipulation of NEDD4-1 expression in different lung cell systems demonstrated that suppression of NEDD4-1 expression significantly reduced proliferation of NSCLC cells in vitro and tumor growth in vivo, whereas NEDD4-1 overexpression facilitated anchorage-dependent and independent growth in vitro of nontransformed lung epithelial cells that lack pRB and TP53 (BEAS-2B). NEDD4-1 overexpression also augmented the tumorigenicity of lung cancer cells that have an intact PTEN gene (NCI-H460 cells).",
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AU - Franco, Renato

AU - Botti, Gerardo

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AU - De Rosa, Nicla

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