EI24 regulates epithelial-to-mesenchymal transition and tumor progression by suppressing TRAF2-mediated NF-κB activity.

Abstract

Tumor metastasis is a multistep process that requires the concerted activity of discrete biological functions. The epithelial-to-mesenchymal transition (EMT) is the most critical mechanism implicated in tumor progression that is controlled by the inflammatory microenvironment. Understanding how an inflammatory microenvironment is maintained and contributes to tumor progression will be crucial for the development of new effective therapies. Here, we report that etoposide induced 2.4 (EI24) has a multifaceted role against tumor progression that is regulated by both EMT and inflammation. Decreased expression levels of EI24 in epithelial tumor cells induced EMT in association with increased cell motility and invasiveness and resistance to anoikis. Overexpression of EI24 resulted in the opposite cell biological characteristics and suppressed in vivometastatic behavior. EI24 attenuated NF-κB activity by binding to the Complex I component TRAF2 and inducing its lysosome-dependent degradation, leading to transcriptional alterations of EMT- and inflammation-related genes. Analysis of clinical samples demonstrated that reduced EI24 expression and copy number was positively correlated with tumor malignancy and poor prognosis. Collectively, these findings establish EI24 as a critical suppressor of tumor progression and implicate EI24 expression level in malignant tumors as a useful therapeutic and diagnostic marker.

• Authors: Jung-Min Choi, Sushil Devkota, Young Hoon Sung, Han-Woong Lee
• Journal: Oncotarget (Oncotarget) Vol. 4 Issue 12 Pg. 2383-96 (Dec 2013) ISSN: 1949-2553 [Electronic] United States
• PMID: 24280371 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• EI24 protein, human
• EI24 protein, mouse
• NF-kappa B
• Nuclear Proteins
• TNF Receptor-Associated Factor 2

Topics

• Animals
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (physiology)
• Disease Progression
• Epithelial-Mesenchymal Transition
• Female
• Humans
• Melanoma, Experimental (genetics, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• TNF Receptor-Associated Factor 2 (genetics, metabolism)
• Transfection