Association of ATF4 Expression With Tissue Hypoxia and M2 Macrophage Infiltration in Infantile Hemangioma
Association of ATF4 Expression With Tissue Hypoxia and M2 Macrophage Infiltration in Infantile Hemangioma
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ATF4 表达与婴儿血管瘤组织缺氧和 M2 巨噬细胞浸润的关系
DOI：
10.1369/0022155417694872
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发表时间：
2017
影响因子：
3.2
通讯作者：
Zhao Ji hong
中科院分区：
文献类型：
--
作者：
Xia Hou fu;Zhu Jun yi;Wang Jing nan;Ren Jian gang;Cai Yu;Wang Feng qin;Zhang Wei;Chen Gang;Zhao Yi fang;Zhao Ji hong
越来越多的研究揭示了缺氧条件及其在婴儿血管瘤（IH）（婴儿期最常见的良性肿瘤）独特进展中的关键作用。转录激活因子4（Activating transcription factor 4，ATF 4）是介导细胞对各种应激信号适应的重要基因，可赋予肿瘤细胞在缺氧条件下的生存优势，并调节肿瘤的进展。然而，ATF 4在IH中的潜在作用仍然未知。本研究采用免疫组化和免疫荧光双标记法检测了27例IH组织中缺氧诱导因子（HIF）-1α、ATF 4和巨噬细胞集落刺激因子（M-CSF）的表达，并进行了斯皮尔曼等级相关检验。我们的研究结果表明，HIF-1α、ATF 4和M-CSF的表达在增殖型IH中比在退化型IH中显著上调。HIF-1α、ATF 4与ATF 4、M-CSF呈平行正相关，且表达同步。此外，我们的体外研究表明，缺氧明显上调血管瘤干细胞中HIF-1α、ATF 4和M-CSF的表达。最重要的是，它们的表达与IH中M2极化巨噬细胞的百分比一致相关。所有这些结果和已建立的证据表明，缺氧诱导的ATF 4表达可能通过M-CSF诱导的M2极化巨噬细胞浸润促进增殖性IH的进展。
Accumulating studies have revealed the hypoxic condition and its crucial role in the distinctive progression of infantile hemangioma (IH), the most common benign tumor in infancy. Activating transcription factor 4 (ATF4), an important gene mediating cellular adaptation to various stress signals, could confer a survival advantage for tumor cells under hypoxia and regulate tumor progression. However, the potential role of ATF4 in IH was still unknown. In this study, the expression of hypoxia inducible factor (HIF)-1α, ATF4, and macrophage colony-stimulating factor (M-CSF) in 27 specimens of IH was measured by immunochemistry and double-labeling immunofluorescence, followed by the Spearman rank correlation test. Our results showed that the expression of HIF-1α, ATF4, and M-CSF was significantly upregulated in proliferating IH compared with involuting IH. Meanwhile, HIF-1α and ATF4, in parallel with ATF4 and M-CSF, exhibited positive correlation and synchronous expression. In addition, our in vitro studies demonstrated that hypoxia obviously upregulated the expression of HIF-1α, ATF4, and M-CSF in hemangioma stem cells. Most importantly, their expression was uniformly correlated with the percentage of M2-polarized macrophages in IH. All those results and established evidence indicated that hypoxia-induced ATF4 expression may promote progression of proliferating IH through M-CSF-induced M2-polarized macrophages infiltration.