TRAF4 promotes lung cancer aggressiveness by modulating tumormicroenvironment in normal fibroblasts

Collection with item attached
2017
Item details URL
http://open-repository.kisti.re.kr/cube/handle/open_repository/486387.do
DOI
10.1038/s41598-017-09447-z
Title
TRAF4 promotes lung cancer aggressiveness by modulating tumormicroenvironment in normal fibroblasts
Description
This work was supported by Radiation Technology R&D program through theNational Research Foundation of Korea funded by the Ministry of Science,ICT & Future Planning (2017M2A2A7A01019304) and Basic Science ResearchProgram through the National Research Foundation of Korea (NRF) fundedby the Ministry of Education (2017R1D1A1B03028769).
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-.B-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 epithelialmesenchymal 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.
provenance
Made available in Cube on 2018-09-28T16:06:15Z (GMT). No. of bitstreams: 0
language
English
author
Kim, EunGi
Kim, Wanyeon
Lee, Sungmin
Chun, Jahyun
Kang, JiHoon
Park, Gaeul
Han, IkJoon
Yang, Hee Jung
Youn, HyeSook
Youn, BuHyun
accessioned
2018-09-28T16:06:15Z
available
2018-09-28T16:06:15Z
issued
2017
citation
SCIENTIFIC REPORTS(7)
issn
2045-2322
uri
http://open-repository.kisti.re.kr/cube/handle/open_repository/486387.do
Funder
교육부
Funding Program
BK21플러스사업(0.5)
Project ID
1345273982
Jurisdiction
Rep.of Korea
Project Name
Research Group Longevity and Marine Biotechnology
rights
openAccess
type
article


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