Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression.
Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression.
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DOI：
10.7150/thno.17895
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发表时间：
2017
期刊：
影响因子：
12.4
通讯作者：
Hsieh CH
中科院分区：
文献类型：
--
作者：
Lin YJ;Shyu WC;Chang CW;Wang CC;Wu CP;Lee HT;Chen LJ;Hsieh CH
叉头框 C1 (FOXC1) 是转录因子叉头家族的成员，其特点是具有 DNA 结合叉头结构域。越来越多的证据表明 FOXC1 参与肿瘤进展。然而，肿瘤缺氧在 FOXC1 调节中的作用及其对肺癌进展的影响尚不清楚。在此，我们报告 FOXC1 在啮齿动物或人类肺癌组织的缺氧区域中表达上调。缺氧应激显着诱导 FOXC1 表达。此外，缺氧通过缺氧诱导因子-1α（HIF-1α）与FOXC1启动子中的缺氧反应元件（HRE）直接结合来激活FOXC1转录。 FOXC1在肺癌细胞中的功能获得在体外促进细胞增殖、迁移、侵袭、血管生成和上皮间质转化。然而，肺癌细胞中 FOXC1 的敲除抑制了这些作用。值得注意的是，在肺癌异种移植模型中，通过 HIF-1 介导的 FOXC1 shRNA 敲低肿瘤缺氧诱导的 FOXC1 表达，可抑制肿瘤生长和血管生成。最后，封装在脂质纳米颗粒中的 FOXC1 siRNA 的全身递送抑制了肺癌小鼠的肿瘤生长并延长了生存时间。综上所述，这些数据表明 FOXC1 是一种新型缺氧诱导的转录因子，在肿瘤微环境促进的肺癌进展中发挥着关键作用。全身性 FOXC1 阻断疗法可能是肺癌的有效治疗策略。
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.