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Epithelial-mesenchymal transition induced by TNF-? requires NF-?B-mediated transcriptional upregulation of Twist1.

ABSTRACT: Proinflammatory cytokines produced in the tumor microenvironment facilitate tumor development and metastatic progression. In particular, TNF-? promotes cancer invasion and angiogenesis associated with epithelial-mesenchymal transition (EMT); however, the mechanisms underlying its induction of EMT in cancer cells remain unclear. Here we show that EMT and cancer stemness properties induced by chronic treatment with TNF-? are mediated by the upregulation of the transcriptional repressor Twist1. Exposure to TNF-? rapidly induced Twist1 mRNA and protein expression in normal breast epithelial and breast cancer cells. Both IKK-? and NF-?B p65 were required for TNF-?-induced expression of Twist1, suggesting the involvement of canonical NF-?B signaling. In support of this likelihood, we defined a functional NF-?B-binding site in the Twist1 promoter, and overexpression of p65 was sufficient to induce transcriptional upregulation of Twist1 along with EMT in mammary epithelial cells. Conversely, suppressing Twist1 expression abrogated p65-induced cell migration, invasion, EMT, and stemness properties, establishing that Twist1 is required for NF-?B to induce these aggressive phenotypes in breast cancer cells. Taken together, our results establish a signaling axis through which the tumor microenvironment elicits Twist1 expression to promote cancer metastasis. We suggest that targeting NF-?B-mediated Twist1 upregulation may offer an effective a therapeutic strategy for breast cancer treatment.

SUBMITTER: Li CW

PROVIDER: S-EPMC3350107 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Epithelial-mesenchymal transition induced by TNF-α requires NF-κB-mediated transcriptional upregulation of Twist1.

Li Chia-Wei CW Xia Weiya W Huo Longfei L Lim Seung-Oe SO Wu Yun Y Hsu Jennifer L JL Chao Chi-Hong CH Yamaguchi Hirohito H Yang Neng-Kai NK Ding Qingqing Q Wang Yan Y Lai Yun-Ju YJ LaBaff Adam M AM Wu Ting-Jung TJ Lin Been-Ren BR Yang Muh-Hwa MH Hortobagyi Gabriel N GN Hung Mien-Chie MC

Cancer research 20120117 5

Proinflammatory cytokines produced in the tumor microenvironment facilitate tumor development and metastatic progression. In particular, TNF-α promotes cancer invasion and angiogenesis associated with epithelial-mesenchymal transition (EMT); however, the mechanisms underlying its induction of EMT in cancer cells remain unclear. Here we show that EMT and cancer stemness properties induced by chronic treatment with TNF-α are mediated by the upregulation of the transcriptional repressor Twist1. Exp ...[more]

PMID: 22253230

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Project description:Cystic fibrosis (CF) is a monogenetic disease resulting from mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene encoding an anion channel. Recent evidence indicates that CFTR plays a role in other cellular processes, namely in development, cellular differentiation and wound healing. Accordingly, CFTR has been proposed to function as a tumour suppressor in a wide range of cancers. Along these lines, CF was recently suggested to be associated with epithelial-mesenchymal transition (EMT), a latent developmental process, which can be re-activated in fibrosis and cancer. However, it is unknown whether EMT is indeed active in CF and if EMT is triggered by dysfunctional CFTR itself or a consequence of secondary complications of CF. In this study, we investigated the occurrence of EMT in airways native tissue, primary cells and cell lines expressing mutant CFTR through the expression of epithelial and mesenchymal markers as well as EMT-associated transcription factors. Transepithelial electrical resistance, proliferation and regeneration rates, and cell resistance to TGF-β1induced EMT were also measured. CF tissues/cells expressing mutant CFTR displayed several signs of active EMT, namely: destructured epithelial proteins, defective cell junctions, increased levels of mesenchymal markers and EMT-associated transcription factors, hyper-proliferation and impaired wound healing. Importantly, we found evidence that the mutant CFTR triggered EMT was mediated by EMT-associated transcription factor TWIST1. Further, our data show that CF cells are over-sensitive to EMT but the CF EMT phenotype can be reversed by CFTR modulator drugs. Altogether, these results identify for the first time that EMT is intrinsically triggered by the absence of functional CFTR through a TWIST1 dependent mechanism and indicate that CFTR plays a direct role in EMT protection. This mechanistic link is a plausible explanation for the high incidence of fibrosis and cancer in CF, as well as for the role of CFTR as tumour suppressor protein.

Dataset Information

Epithelial-mesenchymal transition induced by TNF-? requires NF-?B-mediated transcriptional upregulation of Twist1.

Publications

Epithelial-mesenchymal transition induced by TNF-α requires NF-κB-mediated transcriptional upregulation of Twist1.

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