Macrophages promote benzopyrene-induced tumor transformation of human bronchial epithelial cells by activation of NF-κB and STAT3 signaling in a bionic airway chip culture and in animal models

// Encheng Li 1,* , Zhiyun Xu 1,* , Hui Zhao 2,* , Zhao Sun 1 , Lei Wang 3 , Zhe Guo 1 , Yang Zhao 1 , Zhancheng Gao 4 and Qi Wang 1 1 Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China 2 Department of Physical Examination Center, The Second Affiliated Hospital, Dalian Medical University, Dalian, China 3 The Liaoning Provincial Key Laboratory for Micro/Nano Technology, Dalian University of Technology, Dalian, China 4 Department of Respiratory & Critical Care Medicine, The People’s Hospital of Peking University, Beijing, China * These authors contributed equally to this work Correspondence to: Qi Wang, email: // Zhancheng Gao, email: // Keywords : Macrophages, malignant transformation, NF-κB, STAT3, microfluidic chip Received : January 02, 2015 Accepted : February 12, 2015 Published : March 12, 2015 Abstract We investigated the role of macrophages in promoting benzopyrene (BaP)-induced malignant transformation of human bronchial epithelial cells using a BaP-induced tumor transformation model with a bionic airway chip in vitro and in animal models. The bionic airway chip culture data showed that macrophages promoted BaP-induced malignant transformation of human bronchial epithelial cells, which was mediated by nuclear factor (NF)-κB and STAT3 pathways to induce cell proliferation, colony formation in chip culture, and tumorigenicity in nude mice. Blockage of interleukin (IL)-6 or tumor necrosis factor (TNF)-α signaling or inhibition of NF-κB, STAT3, or cyclinD1 expression abrogated the effect of macrophages on malignant transformation in the bionic airway chip culture. In vivo , macrophages promoted lung tumorigenesis in a carcinogen-induced animal model. Similarly, blockage of NF-κB, STAT3, or cyclinD1 using siRNA transfection decreased the carcinogen-induced tumorigenesis in rats. We demonstrated that macrophages are critical in promoting lung tumorigenesis and that the macrophage-initiated TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways are primarily responsible for promoting lung tumorigenesis.