MEKK3 Sustains EMT and Stemness in Pancreatic Cancer by Regulating YAP and TAZ Transcriptional Activity.

BACKGROUND/AIM:Pancreatic cancer is one of the most threatening and poorly understood human malignancies. MEKK3 (MAP3K3) is a serine/threonine kinase activated by different signaling pathways. YAP and TAZ are critical oncogenic effectors in pancreatic cancer. We hypothesized that MEKK3 could sustain pancreatic cancer by inducing YAP/TAZ oncogenic activities. MATERIALS AND METHODS:In Panc1 and AsPC1 pancreatic cancer cell lines MEKK3 was knocked-out (KO) by the CRISPR/Cas9 method. These cells were used to evaluate MEKK3 contribution to the expression of YAP/TAZ and their target genes, cell migration, stemness, and in vivo tumor growth. RESULTS:MEKK3 KO reduced both EMT and cell migration, the size of 3D colonies and the percentage of CD44⁺/CD24⁺/EpCAM⁺ CSC, promoter recruitment of YAP/TAZ and the expression of their target genes. It reduced tumor growth and prolonged mice overall survival. CONCLUSION:Silencing of MEKK3 represents a valid approach to revert in vivo the aggressiveness of pancreatic cancer by modulating YAP/TAZ transcriptional activities. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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