| Summary: | 博士 === 國立中興大學 === 分子生物學研究所 === 105 === Purpose: Forkhead box C1 (FOXC1) belongs to the forkhead family of transcription factors which with helix-turn-helix forkhead-like DNA binding domain. More and more reports indicate that FOXC1 is involved in various tumor progressions. However, the mechanism of tumor hypoxia in FOXC1 regulation and its role on lung cancer progression remain unclear.
Results: We find that the expression of FOXC1 was increased in hypoxic areas of lung cancer tissues from rodents or humans. Hypoxia activated FOXC1 transcription through binding of hypoxia-inducible factor-1α (HIF-1α) to the hypoxia-responsive element (HRE) in the FOXC1 promoter via chromatin immunoprecipitation assay. FOXC1 overexpression in lung cancer CL1-0 cells promoted proliferation, migration, invasion, angiogenesis, and epithelial–mesenchymal transition in vitro, whereas FOXC1 shRNA in lung cancer CL1-5 cells inhibited these effects. Moreover, we used specific HIF-1-mediated FOXC1 shRNAs in lung cancer xenograft models to knockdown the tumor hypoxia-induced FOXC1 expression and could suppress tumor growth and angiogenesis through immunofluorescence staining. Finally, systemic delivery of FOXC1 siRNA with 2’-O-methyl modification encapsulated in lipid nanoparticles from tail vein inhibited tumor growth and increased survival time in lung cancer xenograft mice.
Conclusion: These results point out that FOXC1 is a novel hypoxia response gene and plays a critical transcriptional role in tumor microenvironment which promoted lung cancer progression. Systemic delivery FOXC1 siRNA to decrease FOXC1 expression may be an effective therapeutic development for lung cancer.
Keywords: Tumor hypoxia, HIF-1α, Lung cancer, FOXC1
|
|---|
