FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis
FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis
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DOI：
10.1172/jci87631
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发表时间：
2018-06-01
影响因子：
15.9
通讯作者：
Peters-Golden, Marc
中科院分区：
文献类型：
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作者：
Penke, Loka R.;Speth, Jennifer M.;Peters-Golden, Marc
虽然转录因子叉头盒M1 （FOXM1）是众所周知的原癌基因，但其在肺成纤维细胞激活中的潜在作用从未被探索过。在这里，我们发现FOXM1在人类和小鼠的纤维化肺成纤维细胞中比在正常肺成纤维细胞中表达得更高。FOXM1不仅是细胞增殖对丝裂原的反应所必需的，也是肌成纤维细胞分化和tgf - β诱导的细胞凋亡抵抗所必需的。脂质介质pge2通过cAMP信号传导作用，被确定为FOXM1的内源性负调节因子。最后，在成纤维细胞中基因缺失FOXM1或在治疗方案中给予FOXM1抑制剂Siomycin A可减轻博来霉素诱导的肺纤维化。我们的研究结果确定FOXM1是肺成纤维细胞激活的驱动因素，并强调了针对FOXM1治疗肺纤维化的治疗潜力。
While the transcription factor forkhead box M1 (FOXM1) is well known as a proto-oncogene, its potential role in lung fibroblast activation has never been explored. Here, we show that FOXM1 is more highly expressed in fibrotic than in normal lung fibroblasts in humans and mice. FOXM1 was required not only for cell proliferation in response to mitogens, but also for myofibroblast differentiation and apoptosis resistance elicited by TGF-beta. The lipid mediator PGE 2, acting via cAMP signaling, was identified as an endogenous negative regulator of FOXM1. Finally, genetic deletion of FOXM1 in fibroblasts or administration of the FOXM1 inhibitor Siomycin A in a therapeutic protocol attenuated bleomycin-induced pulmonary fibrosis. Our results identify FOXM1 as a driver of lung fibroblast activation and underscore the therapeutic potential of targeting FOXM1 for pulmonary fibrosis.