IL-1   β    induces ZEB1 and Slug and downregulates E-cadherin in NSCLC Free

4668

Loss of E-cadherin is the hallmark of epithelial mesenchymal transition (EMT), a process originally described in embryogenesis but now recognized as a central element of carcinogenesis. The loss of E-cadherin confers a more invasive phenotype and is one of the steps leading to metastasis. In this study, we show that the pro-inflammatory cytokine, interleukin-1β (IL-1β), induces the downregulation of E-cadherin protein (an epithelial marker) in non-small cell lung cancer (NSCLC) cell lines in a concentration- and time-dependent manner. IL-1β treatment of NSCLC also leads to the upregulation of vimentin, a mesenchymal marker. Although inactivating mutations or promoter hypermethylation have been observed to account for loss of E-cadherin function in some malignancies, transcriptional repression has emerged as one of the important mechanisms for the downregulation of E-cadherin expression during tumor development and progression. Recently, several E-cadherin transcriptional repressors have been characterized (ZEB1, Snail, E12/E47, Slug, Twist and SIP-1) and shown to interact with the proximal E-boxes of the E-cadherin promoter. Here we show that treatment of NSCLC cell lines with IL-1β leads to an increase in the mRNA expression of the E-cadherin transcriptional repressors, ZEB1 and Slug and a decrease in E-cadherin expression. Inhibition of ZEB1 expression with small-interfering RNA abrogated the IL-1β-dependent inhibition of E-cadherin. Thus IL-1β downregulates E-cadherin and induces EMT in NSCLC by inducing ZEB1 and Slug. This is the first report indicating the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in NSCLC.