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Inflammation and Hras signaling control epithelial-mesenchymal transition during skin tumor progression.

ABSTRACT: Epithelial-mesenchymal transition (EMT) is thought to be an important, possibly essential, component of the process of tumor dissemination and metastasis. About 20%-30% of Hras mutant mouse skin carcinomas induced by chemical initiation/promotion protocols have undergone EMT. Reduced exposure to TPA-induced chronic inflammation causes a dramatic reduction in classical papillomas and squamous cell carcinomas (SCCs), but the mice still develop highly invasive carcinomas with EMT properties, reduced levels of Hras and Egfr signaling, and frequent Ink4/Arf deletions. Deletion of Hras from the mouse germline also leads to a strong reduction in squamous tumor development, but tumors now acquire activating Kras mutations and exhibit more aggressive metastatic properties. We propose that invasive carcinomas can arise by different genetic and biological routes dependent on exposure to chronic inflammation and possibly from different target cell populations within the skin. Our data have implications for the use of inhibitors of inflammation or of Ras/Egfr pathway signaling for prevention or treatment of invasive cancers.

SUBMITTER: Wong CE

PROVIDER: S-EPMC3613613 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Inflammation and Hras signaling control epithelial-mesenchymal transition during skin tumor progression.

Wong Christine E CE Yu Jennifer S JS Quigley David A DA To Minh D MD Jen Kuang-Yu KY Huang Phillips Y PY Del Rosario Reyno R Balmain Allan A

Genes & development 20130301 6

Epithelial-mesenchymal transition (EMT) is thought to be an important, possibly essential, component of the process of tumor dissemination and metastasis. About 20%-30% of Hras mutant mouse skin carcinomas induced by chemical initiation/promotion protocols have undergone EMT. Reduced exposure to TPA-induced chronic inflammation causes a dramatic reduction in classical papillomas and squamous cell carcinomas (SCCs), but the mice still develop highly invasive carcinomas with EMT properties, reduce ...[more]

PMID: 23512660

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Project description:The airway epithelium is a semi-impermeable barrier whose disruption by growth factor reprogramming is associated with chronic airway diseases of humans. Transforming growth factor beta (TGF?)-induced epithelial mesenchymal transition (EMT) plays important roles in airway remodeling characteristic of idiopathic lung fibrosis, asthma and chronic obstructive pulmonary disease (COPD). Inflammation of the airways leads to airway injury and tumor necrosis factor alpha (TNF?) plays an important pro-inflammatory role. Little systematic information about the effects of EMT on TNF? signaling is available. Using an in vitro model of TGF?-induced EMT in primary human small airway epithelial cells (hSAECs), we applied quantitative proteomics and phosphoprotein profiling to understand the molecular mechanism of EMT and the impact of EMT on innate inflammatory responses. We quantified 7925 proteins and 1348 phosphorylation sites by stable isotope labeling with iTRAQ technology. We found that cellular response to TNF? is cell state dependent and the relative TNF? response in mesenchymal state is highly compressed. Combined bioinformatics analyses of proteome and phosphoproteome indicate that the EMT state is associated with reprogramming of kinome, signaling cascade of upstream transcription regulators, phosphor-networks, and NF-?B dependent cell signaling.Epithelial mesenchymal transition and inflammation have important implications for clinical and physiologic manifestations of chronic airway diseases such as severe asthma, COPD, and lung fibrosis. Little systematic information on the interplay between EMT and innate inflammation is available. This study combined quantitative proteomics and phosphorproteomics approach to obtain systems-level insight into the upstream transcription regulators involved in the TGF?-induced EMT in primary human small airway epithelial cells and to elucidate how EMT impacts on the TNF? signaling pathways. The proteomics and phosphoproteomics analysis indicates that many signaling pathways involved in TGF?-induced EMT and EMT has profound reprogramming effects on innate inflammation response.

Dataset Information

Inflammation and Hras signaling control epithelial-mesenchymal transition during skin tumor progression.

Publications

Inflammation and Hras signaling control epithelial-mesenchymal transition during skin tumor progression.

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