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

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-B (NF-B) 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-B 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-B 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-B 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.