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Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression

Forkhead box C1 (FOXC1) is a member of the forkhead family of transcription factors that are characterized by a DNA-binding forkhead domain. Increasing evidence indicates that FOXC1 is involved in tumor progression. However, the role of tumor hypoxia in FOXC1 regulation and its impact on lung cancer...

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Autores principales: Lin, Yu-Jung, Shyu, Woei-Cherng, Chang, Chi-Wei, Wang, Chi-Chung, Wu, Chung-Pu, Lee, Hsu-Tung, Chen, Liang-Jwu, Hsieh, Chia-Hung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399585/
https://www.ncbi.nlm.nih.gov/pubmed/28435457
http://dx.doi.org/10.7150/thno.17895
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author Lin, Yu-Jung
Shyu, Woei-Cherng
Chang, Chi-Wei
Wang, Chi-Chung
Wu, Chung-Pu
Lee, Hsu-Tung
Chen, Liang-Jwu
Hsieh, Chia-Hung
author_facet Lin, Yu-Jung
Shyu, Woei-Cherng
Chang, Chi-Wei
Wang, Chi-Chung
Wu, Chung-Pu
Lee, Hsu-Tung
Chen, Liang-Jwu
Hsieh, Chia-Hung
author_sort Lin, Yu-Jung
collection PubMed
description Forkhead box C1 (FOXC1) is a member of the forkhead family of transcription factors that are characterized by a DNA-binding forkhead domain. Increasing evidence indicates that FOXC1 is involved in tumor progression. However, the role of tumor hypoxia in FOXC1 regulation and its impact on lung cancer progression are unclear. Here, we report that FOXC1 was upregulated in hypoxic areas of lung cancer tissues from rodents or humans. Hypoxic stresses significantly induced FOXC1 expression. Moreover, hypoxia activated FOXC1 transcription via direct binding of hypoxia-inducible factor-1α (HIF-1α) to the hypoxia-responsive element (HRE) in the FOXC1 promoter. FOXC1 gain-of-function in lung cancer cells promoted cell proliferation, migration, invasion, angiogenesis, and epithelial-mesenchymal transition in vitro. However, a knockdown of FOXC1 in lung cancer cells inhibited these effects. Notably, knockdown of tumor hypoxia-induced FOXC1 expression via HIF-1-mediated FOXC1 shRNAs in lung cancer xenograft models suppressed tumor growth and angiogenesis. Finally, systemic delivery of FOXC1 siRNA encapsulated in lipid nanoparticles inhibited tumor growth and increased survival time in lung cancer-bearing mice. Taken together, these data indicate that FOXC1 is a novel hypoxia-induced transcription factor and plays a critical role in tumor microenvironment-promoted lung cancer progression. Systemic FOXC1 blockade therapy may be an effective therapeutic strategy for lung cancer.
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spelling pubmed-53995852017-04-21 Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression Lin, Yu-Jung Shyu, Woei-Cherng Chang, Chi-Wei Wang, Chi-Chung Wu, Chung-Pu Lee, Hsu-Tung Chen, Liang-Jwu Hsieh, Chia-Hung Theranostics Research Paper Forkhead box C1 (FOXC1) is a member of the forkhead family of transcription factors that are characterized by a DNA-binding forkhead domain. Increasing evidence indicates that FOXC1 is involved in tumor progression. However, the role of tumor hypoxia in FOXC1 regulation and its impact on lung cancer progression are unclear. Here, we report that FOXC1 was upregulated in hypoxic areas of lung cancer tissues from rodents or humans. Hypoxic stresses significantly induced FOXC1 expression. Moreover, hypoxia activated FOXC1 transcription via direct binding of hypoxia-inducible factor-1α (HIF-1α) to the hypoxia-responsive element (HRE) in the FOXC1 promoter. FOXC1 gain-of-function in lung cancer cells promoted cell proliferation, migration, invasion, angiogenesis, and epithelial-mesenchymal transition in vitro. However, a knockdown of FOXC1 in lung cancer cells inhibited these effects. Notably, knockdown of tumor hypoxia-induced FOXC1 expression via HIF-1-mediated FOXC1 shRNAs in lung cancer xenograft models suppressed tumor growth and angiogenesis. Finally, systemic delivery of FOXC1 siRNA encapsulated in lipid nanoparticles inhibited tumor growth and increased survival time in lung cancer-bearing mice. Taken together, these data indicate that FOXC1 is a novel hypoxia-induced transcription factor and plays a critical role in tumor microenvironment-promoted lung cancer progression. Systemic FOXC1 blockade therapy may be an effective therapeutic strategy for lung cancer. Ivyspring International Publisher 2017-03-05 /pmc/articles/PMC5399585/ /pubmed/28435457 http://dx.doi.org/10.7150/thno.17895 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Lin, Yu-Jung
Shyu, Woei-Cherng
Chang, Chi-Wei
Wang, Chi-Chung
Wu, Chung-Pu
Lee, Hsu-Tung
Chen, Liang-Jwu
Hsieh, Chia-Hung
Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression
title Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression
title_full Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression
title_fullStr Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression
title_full_unstemmed Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression
title_short Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression
title_sort tumor hypoxia regulates forkhead box c1 to promote lung cancer progression
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399585/
https://www.ncbi.nlm.nih.gov/pubmed/28435457
http://dx.doi.org/10.7150/thno.17895
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