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CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation

Through the progressive accumulation of genetic and epigenetic alterations in cellular physiology, non–small-cell lung cancer (NSCLC) evolves in distinct steps involving mutually exclusive oncogenic mutations in K-Ras or EGFR along with inactivating mutations in the p53 tumor suppressor. Herein, we...

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Autores principales: Chavdoula, Evangelia, Habiel, David M, Roupakia, Eugenia, Markopoulos, Georgios S, Vasilaki, Eleni, Kokkalis, Antonis, Polyzos, Alexander P, Boleti, Haralabia, Thanos, Dimitris, Klinakis, Apostolos, Kolettas, Evangelos, Marcu, Kenneth B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892436/
https://www.ncbi.nlm.nih.gov/pubmed/31792060
http://dx.doi.org/10.26508/lsa.201900460
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author Chavdoula, Evangelia
Habiel, David M
Roupakia, Eugenia
Markopoulos, Georgios S
Vasilaki, Eleni
Kokkalis, Antonis
Polyzos, Alexander P
Boleti, Haralabia
Thanos, Dimitris
Klinakis, Apostolos
Kolettas, Evangelos
Marcu, Kenneth B
author_facet Chavdoula, Evangelia
Habiel, David M
Roupakia, Eugenia
Markopoulos, Georgios S
Vasilaki, Eleni
Kokkalis, Antonis
Polyzos, Alexander P
Boleti, Haralabia
Thanos, Dimitris
Klinakis, Apostolos
Kolettas, Evangelos
Marcu, Kenneth B
author_sort Chavdoula, Evangelia
collection PubMed
description Through the progressive accumulation of genetic and epigenetic alterations in cellular physiology, non–small-cell lung cancer (NSCLC) evolves in distinct steps involving mutually exclusive oncogenic mutations in K-Ras or EGFR along with inactivating mutations in the p53 tumor suppressor. Herein, we show two independent in vivo lung cancer models in which CHUK/IKK-α acts as a major NSCLC tumor suppressor. In a novel transgenic mouse strain, wherein IKKα ablation is induced by tamoxifen (Tmx) solely in alveolar type II (AT-II) lung epithelial cells, IKKα loss increases the number and size of lung adenomas in response to the chemical carcinogen urethane, whereas IKK-β instead acts as a tumor promoter in this same context. IKKα knockdown in three independent human NSCLC lines (independent of K-Ras or p53 status) enhances their growth as tumor xenografts in immune-compromised mice. Bioinformatics analysis of whole transcriptome profiling followed by quantitative protein and targeted gene expression validation experiments reveals that IKKα loss can result in the up-regulation of activated HIF-1-α protein to enhance NSCLC tumor growth under hypoxic conditions in vivo.
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spelling pubmed-68924362019-12-06 CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation Chavdoula, Evangelia Habiel, David M Roupakia, Eugenia Markopoulos, Georgios S Vasilaki, Eleni Kokkalis, Antonis Polyzos, Alexander P Boleti, Haralabia Thanos, Dimitris Klinakis, Apostolos Kolettas, Evangelos Marcu, Kenneth B Life Sci Alliance Research Articles Through the progressive accumulation of genetic and epigenetic alterations in cellular physiology, non–small-cell lung cancer (NSCLC) evolves in distinct steps involving mutually exclusive oncogenic mutations in K-Ras or EGFR along with inactivating mutations in the p53 tumor suppressor. Herein, we show two independent in vivo lung cancer models in which CHUK/IKK-α acts as a major NSCLC tumor suppressor. In a novel transgenic mouse strain, wherein IKKα ablation is induced by tamoxifen (Tmx) solely in alveolar type II (AT-II) lung epithelial cells, IKKα loss increases the number and size of lung adenomas in response to the chemical carcinogen urethane, whereas IKK-β instead acts as a tumor promoter in this same context. IKKα knockdown in three independent human NSCLC lines (independent of K-Ras or p53 status) enhances their growth as tumor xenografts in immune-compromised mice. Bioinformatics analysis of whole transcriptome profiling followed by quantitative protein and targeted gene expression validation experiments reveals that IKKα loss can result in the up-regulation of activated HIF-1-α protein to enhance NSCLC tumor growth under hypoxic conditions in vivo. Life Science Alliance LLC 2019-12-02 /pmc/articles/PMC6892436/ /pubmed/31792060 http://dx.doi.org/10.26508/lsa.201900460 Text en © 2019 Chavdoula et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Chavdoula, Evangelia
Habiel, David M
Roupakia, Eugenia
Markopoulos, Georgios S
Vasilaki, Eleni
Kokkalis, Antonis
Polyzos, Alexander P
Boleti, Haralabia
Thanos, Dimitris
Klinakis, Apostolos
Kolettas, Evangelos
Marcu, Kenneth B
CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation
title CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation
title_full CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation
title_fullStr CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation
title_full_unstemmed CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation
title_short CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation
title_sort chuk/ikk-α loss in lung epithelial cells enhances nsclc growth associated with hif up-regulation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892436/
https://www.ncbi.nlm.nih.gov/pubmed/31792060
http://dx.doi.org/10.26508/lsa.201900460
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