NF-κB-Mediated Inflammation Leading to EMT via miR-200c Is Involved in Cell Transformation Induced By Cigarette Smoke Extract

Abstract

Cigarette smoking constitutes a major human health hazard because it is the most important risk factor for lung cancer. Although evidence for smoking-induced lung cancer in humans is strong, the molecular mechanisms by which smoking causes cancer remain to be established. In this investigation, we evaluated the roles of inflammation and the epithelial-mesenchymal transition (EMT) in cigarette smoke extract (CSE)-induced transformation of human bronchial epithelial (HBE) cells. The results showed that chronic exposure to CSE induced EMT and transformation of these cells. Activation of nuclear factor-κB (NF-κB) by CSE increased levels of the proinflammatory interleukin-6 (IL-6), and acute and chronic exposures to CSE caused decreases in miR-200c levels. By blocking NF-κB with Bay11-7082 and IL-6 with anti-IL-6 antibody and enhancement of IL-6 with human recombinant IL-6, we found that the NF-κB signal pathway was involved in CSE-induced increases of IL-6, which suppressed miR-200c expression and promoted EMT. Moreover, IL-6 was necessary for maintenance of CSE-induced transformation and for malignant progression of HBE cells. Finally, blocking of NF-κB with Bay11-7082 prevented CSE-induced EMT and malignant transformation due to decreases of E-cadherin and miR-200c and elevations of IL-6, N-cadherin, and vimentin. Thus, we have defined a link between inflammation and EMT, processes involved in the malignant transformation of cells caused by CSE. This link, mediated through miRNAs, establishes a mechanism for CSE-induced lung carcinogenesis.

Unravelling the complexity of COPD by microRNAs: it's a small world after all

“…Interestingly, they also found a higher miR-101 expression in slides of lung tissue samples from COPD patients compared with controls, suggesting that this miRNA may also play a role in COPD pathogenesis [16]. Another in vitro study showed that CSE exposure of human bronchial epithelial cells leads to a decrease in miR-200c expression [17]. This miRNA was suggested to maintain the epithelial phenotype as it was shown to target the expression of the E-cadherin transcriptional repressors ZEB1 and ZEB2 [37,38].…”

Baicalin Inhibits Lipopolysaccharide-Induced Inflammation Through Signaling NF-κB Pathway in HBE16 Airway Epithelial Cells

“…Compared with the control group, the secretions of inflammatory factors of IL-6, IL-8, and TNF-α were significantly increased in all LPS-treated groups. Now, it is believed that the molecular mechanism of LPS-induced inflammation mainly involves the NF-κB signaling pathway, which may cause acute or chronic inflammation and increase the production of reactive oxygen and nitrogen species and, therefore, result in Toll-like receptor (TLR)-related diseases [16][17][18][19]. Previous studies phospho-NF-B p65/total ratio of our research team investigated the potential antiinflammatory effects of baicalin, and such effects were further confirmed in this study.…”

The Role of Epithelial-Mesenchymal Transition in Chronic Obstructive Pulmonary Disease

“…Cigarette smoke is undoubtedly the driver of EMT in smokers and indeed numerous studies have demonstrated that cigarette smoke extract can induce EMT in cultured airway epithelial cells [Veljkovic et al, 2011;Milara et al, 2013;Wang et al, 2013;Zhao et al, 2013;Eurlings et al, 2014;Shen et al, 2014]. However, cigarette smoke is a complicated mixture of chemicals and compounds, and the specific components responsible for EMT induction remain largely unknown.…”