TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts

Abstract Normal fibroblasts surrounding tumor cells play a crucial role in cancer progression through formation of the tumor microenvironment. Because factors secreted from normal fibroblasts can modulate the tumor microenvironment, it is necessary to identify key factors associated with regulation...

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Autores principales:	EunGi Kim, Wanyeon Kim, Sungmin Lee, Jahyun Chun, JiHoon Kang, Gaeul Park, IkJoon Han, Hee Jung Yang, HyeSook Youn, BuHyun Youn
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7630f768718842549897a5508950886b
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spelling	oai:doaj.org-article:7630f768718842549897a5508950886b2021-12-02T16:06:08ZTRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts10.1038/s41598-017-09447-z2045-2322https://doaj.org/article/7630f768718842549897a5508950886b2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09447-zhttps://doaj.org/toc/2045-2322Abstract Normal fibroblasts surrounding tumor cells play a crucial role in cancer progression through formation of the tumor microenvironment. Because factors secreted from normal fibroblasts can modulate the tumor microenvironment, it is necessary to identify key factors associated with regulation of secreted factors and to investigate the molecular mechanisms contributing to the tumor microenvironment formation process. In this study, we found that radiation induced the expression and K63-linkage poly-ubiquitination of TRAF4 in normal lung fibroblasts. The K63-linkage poly-ubiquitinated TRAF4 formed complexes with NOX2 or NOX4 by mediating phosphorylated p47-phox in normal lung fibroblasts. Moreover, we showed that TRAF4 stabilized NOX complexes by decreasing lysosomal degradation of NOX2 and NOX4 after irradiation. NOX complexes increased endosomal ROS levels that were permeable into cytoplasm, leading to NF-κB-mediated ICAM1 up-regulation. Soluble ICAM1 was subsequently secreted into conditioned media of radiation-activated normal lung fibroblasts. The conditioned media from irradiated normal fibroblasts enhanced proliferation and epithelial-mesenchymal transition of non-small cell lung cancer cells both in vitro and in vivo. These results demonstrate that TRAF4 in irradiated fibroblasts is positively associated with aggressiveness of adjacent cancer cells by altering the tumor microenvironment. Thus, we suggest that regulation of TRAF4 might be a promising strategy for cancer therapy.EunGi KimWanyeon KimSungmin LeeJahyun ChunJiHoon KangGaeul ParkIkJoon HanHee Jung YangHyeSook YounBuHyun YounNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q EunGi Kim Wanyeon Kim Sungmin Lee Jahyun Chun JiHoon Kang Gaeul Park IkJoon Han Hee Jung Yang HyeSook Youn BuHyun Youn TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts
description	Abstract Normal fibroblasts surrounding tumor cells play a crucial role in cancer progression through formation of the tumor microenvironment. Because factors secreted from normal fibroblasts can modulate the tumor microenvironment, it is necessary to identify key factors associated with regulation of secreted factors and to investigate the molecular mechanisms contributing to the tumor microenvironment formation process. In this study, we found that radiation induced the expression and K63-linkage poly-ubiquitination of TRAF4 in normal lung fibroblasts. The K63-linkage poly-ubiquitinated TRAF4 formed complexes with NOX2 or NOX4 by mediating phosphorylated p47-phox in normal lung fibroblasts. Moreover, we showed that TRAF4 stabilized NOX complexes by decreasing lysosomal degradation of NOX2 and NOX4 after irradiation. NOX complexes increased endosomal ROS levels that were permeable into cytoplasm, leading to NF-κB-mediated ICAM1 up-regulation. Soluble ICAM1 was subsequently secreted into conditioned media of radiation-activated normal lung fibroblasts. The conditioned media from irradiated normal fibroblasts enhanced proliferation and epithelial-mesenchymal transition of non-small cell lung cancer cells both in vitro and in vivo. These results demonstrate that TRAF4 in irradiated fibroblasts is positively associated with aggressiveness of adjacent cancer cells by altering the tumor microenvironment. Thus, we suggest that regulation of TRAF4 might be a promising strategy for cancer therapy.
format	article
author	EunGi Kim Wanyeon Kim Sungmin Lee Jahyun Chun JiHoon Kang Gaeul Park IkJoon Han Hee Jung Yang HyeSook Youn BuHyun Youn
author_facet	EunGi Kim Wanyeon Kim Sungmin Lee Jahyun Chun JiHoon Kang Gaeul Park IkJoon Han Hee Jung Yang HyeSook Youn BuHyun Youn
author_sort	EunGi Kim
title	TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts
title_short	TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts
title_full	TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts
title_fullStr	TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts
title_full_unstemmed	TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts
title_sort	traf4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/7630f768718842549897a5508950886b
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_version_	1718385095770898432

TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts

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