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Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma

BACKGROUND: The E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) negatively regulates phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein levels through polyubiquitination and proteolysis, but its significance in lung cancer is still...

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Autores principales: Song, Ying-Hua, Zhang, Cai-Qing, Chen, Fang-Fang, Lin, Xiao-Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Medknow Publications & Media Pvt Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754953/
https://www.ncbi.nlm.nih.gov/pubmed/29271375
http://dx.doi.org/10.4103/0366-6999.221262
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author Song, Ying-Hua
Zhang, Cai-Qing
Chen, Fang-Fang
Lin, Xiao-Yan
author_facet Song, Ying-Hua
Zhang, Cai-Qing
Chen, Fang-Fang
Lin, Xiao-Yan
author_sort Song, Ying-Hua
collection PubMed
description BACKGROUND: The E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) negatively regulates phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein levels through polyubiquitination and proteolysis, but its significance in lung cancer is still unclear. This study investigated the expression and the role of NEDD4-1 in tumor development and chemosensitivity of lung adenocarcinoma (ADC). METHODS: We retrospectively investigated the expression and significance of NEDD4-1, PTEN, and p-Akt proteins in 135 paired ADC and adjacent noncancerous tissue specimens using immunohistochemistry. Furthermore, we evaluated the relationship between NEDD4-1 expression and clinicopathologic characteristics and prognosis. The effects of small interfering RNA against NEDD4-1 on proliferation and chemosensitivity were examined in A549 cells in vitro using 3-(4,5-dimethylthiazol-2-yl) -5-(3-carboxymethoxyphenyl) -2-(4-sulfophenyl)- 2H-tetrazolium method. The ability of migration and invasion of A549 cells was tested by transwell assay. Moreover, reverse-transcription quantitative polymerase chain reaction and Western blotting analyses were used to determine the expression of NEDD4-1, PTEN, phosphoinositide 3-kinase (PI3K)/Akt activity, and its downstream target proteins. RESULTS: NEDD4-1 protein was significantly upregulated in lung ADC tissues, whereas it was weak or negative in normal lung epithelial cells. The expression of NEDD4-1 in ADC (78.5%, 106/135) was significantly much higher than that in adjacent normal lung tissue (13.3%, 29/135, P < 0.01), and it was associated with lymph node metastasis, tumor-node-metastasis (TNM) stage, and chemotherapy resistance. PTEN expression was downregulated in lung ADC (60.7% vs. 100.0% in noncancerous specimens, P = 0.007), and was negatively correlated with lymph node metastasis, histological variants, clinical stage, chemoresistance. In addition, expression of p-Akt in ADC tissues (71.1% 96/135) was much higher than that in adjacent lung epithelial cells (6.7%, 9/135, P < 0.01). Kaplan-Meier and multivariate analysis demonstrated that expressions of NEDD4-1 and PTEN were both independent risk factors for survival in patients with lung ADC. NEDD4-1 knockdown in vivo decreased proliferation, migration, and invasion and improved chemosensitivity to cisplatin and paclitaxel in A549 cells. NEDD4-1 knockdown also significantly enhanced PTEN expression and inhibited p-Akt activity and downstream target proteins. CONCLUSIONS: NEDD4-1 upregulation may contribute to the progression of lung ADC. NEDD4-1 may regulate the proliferation, invasion, migration, and chemoresistance of lung ADC cells through the PI3K/Akt pathway, suggesting that it may be regarded as a therapeutic target for the treatment of lung ADC.
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spelling pubmed-57549532018-01-11 Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma Song, Ying-Hua Zhang, Cai-Qing Chen, Fang-Fang Lin, Xiao-Yan Chin Med J (Engl) Original Article BACKGROUND: The E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) negatively regulates phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein levels through polyubiquitination and proteolysis, but its significance in lung cancer is still unclear. This study investigated the expression and the role of NEDD4-1 in tumor development and chemosensitivity of lung adenocarcinoma (ADC). METHODS: We retrospectively investigated the expression and significance of NEDD4-1, PTEN, and p-Akt proteins in 135 paired ADC and adjacent noncancerous tissue specimens using immunohistochemistry. Furthermore, we evaluated the relationship between NEDD4-1 expression and clinicopathologic characteristics and prognosis. The effects of small interfering RNA against NEDD4-1 on proliferation and chemosensitivity were examined in A549 cells in vitro using 3-(4,5-dimethylthiazol-2-yl) -5-(3-carboxymethoxyphenyl) -2-(4-sulfophenyl)- 2H-tetrazolium method. The ability of migration and invasion of A549 cells was tested by transwell assay. Moreover, reverse-transcription quantitative polymerase chain reaction and Western blotting analyses were used to determine the expression of NEDD4-1, PTEN, phosphoinositide 3-kinase (PI3K)/Akt activity, and its downstream target proteins. RESULTS: NEDD4-1 protein was significantly upregulated in lung ADC tissues, whereas it was weak or negative in normal lung epithelial cells. The expression of NEDD4-1 in ADC (78.5%, 106/135) was significantly much higher than that in adjacent normal lung tissue (13.3%, 29/135, P < 0.01), and it was associated with lymph node metastasis, tumor-node-metastasis (TNM) stage, and chemotherapy resistance. PTEN expression was downregulated in lung ADC (60.7% vs. 100.0% in noncancerous specimens, P = 0.007), and was negatively correlated with lymph node metastasis, histological variants, clinical stage, chemoresistance. In addition, expression of p-Akt in ADC tissues (71.1% 96/135) was much higher than that in adjacent lung epithelial cells (6.7%, 9/135, P < 0.01). Kaplan-Meier and multivariate analysis demonstrated that expressions of NEDD4-1 and PTEN were both independent risk factors for survival in patients with lung ADC. NEDD4-1 knockdown in vivo decreased proliferation, migration, and invasion and improved chemosensitivity to cisplatin and paclitaxel in A549 cells. NEDD4-1 knockdown also significantly enhanced PTEN expression and inhibited p-Akt activity and downstream target proteins. CONCLUSIONS: NEDD4-1 upregulation may contribute to the progression of lung ADC. NEDD4-1 may regulate the proliferation, invasion, migration, and chemoresistance of lung ADC cells through the PI3K/Akt pathway, suggesting that it may be regarded as a therapeutic target for the treatment of lung ADC. Medknow Publications & Media Pvt Ltd 2018-01-05 /pmc/articles/PMC5754953/ /pubmed/29271375 http://dx.doi.org/10.4103/0366-6999.221262 Text en Copyright: © 2017 Chinese Medical Journal http://creativecommons.org/licenses/by-nc-sa/3.0 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
spellingShingle Original Article
Song, Ying-Hua
Zhang, Cai-Qing
Chen, Fang-Fang
Lin, Xiao-Yan
Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma
title Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma
title_full Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma
title_fullStr Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma
title_full_unstemmed Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma
title_short Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma
title_sort upregulation of neural precursor cell expressed developmentally downregulated 4-1 is associated with poor prognosis and chemoresistance in lung adenocarcinoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754953/
https://www.ncbi.nlm.nih.gov/pubmed/29271375
http://dx.doi.org/10.4103/0366-6999.221262
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