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      Association of ATF4 Expression With Tissue Hypoxia and M2 Macrophage Infiltration in Infantile Hemangioma

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          Abstract

          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.

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          Author and article information

          Journal
          J Histochem Cytochem
          J. Histochem. Cytochem
          JHC
          spjhc
          Journal of Histochemistry and Cytochemistry
          SAGE Publications (Sage CA: Los Angeles, CA )
          0022-1554
          1551-5044
          1 February 2017
          May 2017
          : 65
          : 5
          : 285-294
          Affiliations
          [1-0022155417694872]The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education (H-FX, J-YZ, J-NW, J-GR, YC, F-QW, WZ, GC, Y-FZ, J-HZ), School and Hospital of Stomatology, Wuhan University, Wuhan, China
          [2-0022155417694872]Department of Oral and Maxillofacial Surgery (J-GR, YC, WZ, GC, Y-FZ, J-HZ), School and Hospital of Stomatology, Wuhan University, Wuhan, China
          Author notes
          [*]

          Authors contributed equally to this article.

          [*]Yi-fang Zhao or Ji-hong Zhao, School and Hospital of Stomatology, Wuhan University, No. 237 Luoyu Road, Wuhan 430079, China.E-mails: yifang@ 123456whu.edu.cn (Y-FZ); jhzhao988@ 123456foxmail.com (J-HZ)
          Article
          PMC5407535 PMC5407535 5407535 10.1369_0022155417694872
          10.1369/0022155417694872
          5407535
          28438094
          114d3400-2228-42e0-93aa-268441b593f5
          © The Author(s) 2017
          History
          : 9 November 2016
          : 24 January 2017
          Funding
          Funded by: National Natural Science Foundation of China, FundRef http://dx.doi.org/10.13039/501100001809;
          Award ID: 81570994
          Award ID: 81600385
          Award ID: 81671008
          Categories
          Articles

          macrophage,ATF4,HIF-1α,infantile hemangioma,M-CSF
          macrophage, ATF4, HIF-1α, infantile hemangioma, M-CSF

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