Elevated ATF4 Expression in Odontogenic Keratocysts Epithelia: Potential Involvement in Tissue Hypoxia and Stromal M2 Macrophage Infiltration
Elevated ATF4 Expression in Odontogenic Keratocysts Epithelia: Potential Involvement in Tissue Hypoxia and Stromal M2 Macrophage Infiltration
复制标题
牙源性角化囊肿上皮细胞中 ATF4 表达升高：可能参与组织缺氧和基质 M2 巨噬细胞浸润
DOI：
10.1369/0022155419871550
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发表时间：
2019
影响因子：
3.2
通讯作者：
Zhao Ji Hong
中科院分区：
文献类型：
--
作者：
Zhong Wen Qun;Li Zhi Zheng;Jiang Hao;Zou Yan Ping;Wang Hai Tao;Cai Yu;Zhao Yi;Zhao Ji Hong
本研究旨在探讨转录激活因子4（ATF 4）在牙源性角化囊肿（OKC）中的表达及其与缺氧和M2极化巨噬细胞浸润的关系，以及与OKC血管生成的潜在关系。采用免疫组化法检测ATF 4、低氧诱导因子1α（HIF-1α）、巨噬细胞集落刺激因子（M-CSF）和核因子κ-B受体激活因子配体（RANKL）在OKC和正常口腔黏膜中的表达。同时，用抗CD 31抗体测定微血管密度（MVD）。使用CD 68+和CD 163+双染色鉴定M2极化巨噬细胞。采用斯皮尔曼秩相关检验和分层聚类分析方法，分析ATF 4与HIF-1α、M-CSF和M2极化巨噬细胞浸润的相关性。人永生化口腔上皮细胞（HIOECs）用于体外实验。OKC上皮中HIF-1α、ATF 4和M-CSF的表达较OM显著上调。ATF 4的表达与HIF-1α、M-CSF、MVD、M2极化巨噬细胞浸润呈正相关。ATF 4在OKC上皮细胞中的高表达可能促进M2巨噬细胞对缺氧的反应性浸润，导致OKC的发展。
The aim of this study was to investigate the expression of the activating transcription factor 4 (ATF4) in odontogenic keratocysts (OKC), its association with hypoxia and M2-polarized macrophages infiltration, and its potential relationships with angiogenesis in OKC. The expression of ATF4, hypoxia-inducible factor 1α (HIF-1α), macrophage colony-stimulating factor (M-CSF), and receptor activator of nuclear factor κ-B ligand (RANKL) in OKC samples and normal oral mucosa (OM) was detected by immunohistochemistry. Meanwhile, microvessel density (MVD) was measured using antibody against CD31. M2-polarized macrophages were identified using double-staining for CD68+ and CD163+. The correlations of ATF4 with HIF-1α, M-CSF, and M2-polarized macrophages infiltration were determined by Spearman’s rank correlation test and hierarchical clustering. Human immortalized oral epithelial cells (HIOECs) were used in in vitro experiments. Our data showed that the expression of HIF-1α, ATF4, and M-CSF was significantly upregulated in the epithelium of OKC when compared with the OM. The expression of ATF4 was positively correlated with that of HIF-1α, M-CSF, MVD, and M2-polarized macrophages infiltration. Elevated expression of ATF4 in the epithelial lining of OKC may facilitate the M2 macrophages infiltration in response to hypoxia, leading to the development of OKC.