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

• Published in: Scientific reports Vol. 7; no. 1; pp. 8923 - 14
• Main Authors: Kim, EunGi, Kim, Wanyeon, Lee, Sungmin, Chun, Jahyun, Kang, JiHoon, Park, Gaeul, Han, IkJoon, Yang, Hee Jung, Youn, HyeSook, Youn, BuHyun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.08.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 14/34; 631/67/1612/1350; 631/67/1857; 631/67/327; 631/80/458/582; 64/60; 82/80; 96/109; 96/95; Animals; Cell Line, Tumor; Cell proliferation; CYBB protein; Cytoplasm; Disease Progression; Endosomes - metabolism; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Fibroblasts - radiation effects; Gene Expression Regulation; Humanities and Social Sciences; Humans; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - blood; Intercellular Adhesion Molecule-1 - metabolism; Irradiation; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lysosomes; Lysosomes - metabolism; Male; Mesenchyme; Mice; Models, Biological; Molecular modelling; multidisciplinary; NADPH Oxidase 2 - genetics; NADPH Oxidase 2 - metabolism; NADPH Oxidase 4 - genetics; NADPH Oxidase 4 - metabolism; NF-kappa B - metabolism; NF-κB protein; Non-small cell lung carcinoma; NOX4 protein; Protein Binding; Radiation; Radiation, Ionizing; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Signal Transduction; TNF Receptor-Associated Factor 4 - genetics; TNF Receptor-Associated Factor 4 - metabolism; Tumor cells; Tumor Microenvironment - genetics; Tumors; Ubiquitination; Xenograft Model Antitumor Assays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-09447-z

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.