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; Zhiyun Xu; Hui Zhao; Zhao Sun; Lei Wang; Zhe Guo; Yang Zhao; Zhancheng Gao; Qi Wang

doi:10.18632/oncotarget.3561

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

Oncotarget. 2015 Apr 20;6(11):8900-13. doi: 10.18632/oncotarget.3561.

Authors

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

Affiliations

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.

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.

Keywords: NF-κB; STAT3; macrophages; malignant transformation; microfluidic chip.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / pathology*
Aged
Animals
Benzo(a)pyrene
Bronchi / drug effects*
Bronchi / pathology
Carcinoma, Squamous Cell / pathology*
Cell Count
Cell Transformation, Neoplastic / drug effects*
Cell Transformation, Neoplastic / genetics
Cyclin D1 / antagonists & inhibitors
Cyclin D1 / physiology
Epithelial Cells / drug effects
Epithelial Cells / pathology
Female
Humans
Interleukin-6 / antagonists & inhibitors
Interleukin-6 / physiology
Lab-On-A-Chip Devices*
Lung Neoplasms / chemically induced
Lung Neoplasms / pathology*
Macrophages / physiology*
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
NF-kappa B / antagonists & inhibitors
NF-kappa B / genetics
NF-kappa B / physiology*
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / genetics
Neoplasm Proteins / physiology*
Rats
Rats, Wistar
STAT3 Transcription Factor / antagonists & inhibitors
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / physiology*
Tobacco Smoke Pollution / adverse effects
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Tumor Necrosis Factor-alpha / physiology

Substances

CCND1 protein, human
IL6 protein, human
Interleukin-6
NF-kappa B
Neoplasm Proteins
STAT3 Transcription Factor
STAT3 protein, human
Stat3 protein, rat
Tobacco Smoke Pollution
Tumor Necrosis Factor-alpha
Cyclin D1
Benzo(a)pyrene