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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.

Author information

Kim E1, Kim W2,3, Lee S1, Chun J1, Kang J1, Park G1, Han I2, Yang HJ1, Youn H4, Youn B5,6.

1Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea.2Department of Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea.3Department of Biology Education, Korea National University of Education, Cheongju, 28173, Republic of Korea.4Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, 05006, Republic of Korea.5Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea. bhyoun72@pusan.ac.kr.6Department of Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea. bhyoun72@pusan.ac.kr.