FoxM1 is regulated by both HIF-1 and HIF-2 and contributes to gastrointestinal stromal tumor progression
FoxM1 is regulated by both HIF-1 and HIF-2 and contributes to gastrointestinal stromal tumor progression
复制标题
FoxM1 受 HIF-1α 和 HIF-2α 调节，有助于胃肠道间质瘤的进展
DOI：
10.1007/s10120-018-0846-6
复制
发表时间：
2019-01-01
期刊：
影响因子：
7.4
通讯作者：
Zheng, Jianming
中科院分区：
文献类型：
--
作者：
Bai, Chenguang;Liu, Xiaohong;Zheng, Jianming
背景FoxM 1在多种疾病中发挥重要的调控作用。方法采用免疫组化、实时荧光定量PCR、western blot、CCK-8、创伤愈合试验和Matrigel侵袭试验检测FoxM 1在胃肠道间质瘤（GIST）组织和细胞中的表达，并分析其生物学功能。结果FoxM 1在高度增殖和迁移/侵袭性GIST中高表达。GIST组织中FoxM 1的表达上调与HIF-1α和HIF-2α的表达以及低氧诱导的GIST细胞FoxM 1的表达呈正相关。在功能上，异位表达FoxM 1显著促进GIST细胞增殖、细胞周期进展、迁移和侵袭，而敲低缺氧GIST细胞的内源性FoxM 1具有相反的作用。在分子水平上，常氧条件下FoxM 1受HIF-2α的调控，而缺氧条件下FoxM 1受HIF-1α和HIF-2α的上调。移植瘤数据进一步证实了HIF-1α和HIF-2α对FoxM 1的调节作用，并证明HIF-1α和HIF-2α同时下调可抑制GIST肿瘤的生长。这些发现将FoxM 1确定为设计新型治疗方法以控制GIST进展的可能的新分子靶点。
BackgroundFoxM1 plays important regulatory roles in a variety of diseases. However, the functional role of FoxM1 and mechanisms responsible for its expression in gastrointestinal stromal tumor (GIST) is not thoroughly understood.MethodsFoxM1 protein expression and biological function were examined in human GIST tissues and cells using immunohistochemistry, quantitative real-time PCR, western blot, CCK-8, wound-healing- and Matrigel invasion assays, respectively. The role of hypoxia-inducible factor (HIF) signaling in FoxM1 expression was investigated using chromatin immunoprecipitation and luciferase reporter and in vivo tumor growth assays.ResultsFoxM1 was highly expressed in highly proliferative and migratory/invasive GIST specimens. Upregulation of FoxM1 was positively correlated with the expression of HIF-1α and HIF-2α in GIST specimens, and hypoxia-induced FoxM1 expression in GIST cells. Functionally, ectopic expression of FoxM1 significantly promoted GIST cell proliferation, cell cycle progression, migration and invasion, whereas the knockdown of endogenous FoxM1 of hypoxic GIST cells had the opposite effects. Molecularly, FoxM1 was transcriptionally regulated by HIF-2α under normoxia, whereas it was upregulated by both HIF-1α and HIF-2α under hypoxia. The xenograft tumor data further confirmed the regulated effect of HIF-1α and HIF-2α on FoxM1, and demonstrated that the simultaneous downregulation of both HIF-1α and HIF-2α inhibited GIST tumor growth.ConclusionsOur data demonstrated the critical role of FoxM1 in promoting GIST progression and uncovered a novel HIF-1α/HIF-2α-FoxM1 axis. These findings identify FoxM1 as a possible new molecular target for designing novel therapeutic treatments to control GIST progression.