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標題: Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression
作者: Lin, Yu-Jung
Shyu, Woei-Cherng
Chang, Chi-Wei
Wang, Chi-Chung
Wu, Chung-Pu
Lee, Hsu-Tung
Chen, Liang-Jwu
Hsieh, Chia-Hung
關鍵字: fork head box C1;hypoxia-inducible factor-1α.;lung cancer;tumor hypoxia;Animals;Antineoplastic Agents;Cell Line, Tumor;Cell Movement;Cell Proliferation;DNA;Disease Models, Animal;Disease Progression;Epithelial-Mesenchymal Transition;Forkhead Transcription Factors;Heterografts;Humans;Hypoxia-Inducible Factor 1, alpha Subunit;Liposomes;Lung Neoplasms;Mice;Promoter Regions, Genetic;Protein Binding;RNA, Small Interfering;Transcriptional Activation;Treatment Outcome;Tumor Hypoxia
Project: Theranostics, Volume 7, Issue 5, Page(s) 1177-1191.
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.
DOI: 10.7150/thno.17895
Appears in Collections:分子生物學研究所

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