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
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Encheng Li1,*, Zhiyun Xu1,*, Hui Zhao2,*, Zhao Sun1, Lei Wang3, Zhe Guo1, Yang Zhao1, Zhancheng Gao4 and Qi Wang1
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
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
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.
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