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HGF/c-Met signaling promotes liver progenitor cell migration and invasion by an epithelial-mesenchymal transition-independent, phosphatidyl inositol-3 kinase-dependent pathway in an in vitro model

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Suárez Causado, Amileth and Caballero Díaz, D. and Bertrán, E. and Roncero Romero, César and Addante, Annalisa and García Álvaro, M. and Fernández García de Castro, M. and Herrera González, Blanca and Porras Gallo, Almudena and Fabregat, I. and Sánchez Muñoz, Aránzazu (2015) HGF/c-Met signaling promotes liver progenitor cell migration and invasion by an epithelial-mesenchymal transition-independent, phosphatidyl inositol-3 kinase-dependent pathway in an in vitro model. BBA - Molecular Cell Research . ISSN 0167-4889 (In Press)

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Official URL: http://dx. doi.org/10.1016/j.bbamcr.2015.05.017




Abstract

Oval cells constitute an interesting hepatic cell population. They contribute to sustain liver regeneration during chronic liver damage, but in doing this they can be target of malignant conversion and become tumor-initiating cells and drive hepatocarcinogenesis. The molecular mechanisms beneath either their pro-regenerative or pro-tumorigenic potential are still poorly understood. In this study, we have investigated the role of the HGF/c-Met pathway in regulation of oval cell migratory and invasive properties. Our results show that HGF induces c-Met-dependent oval cell migration both in normal culture conditions and after in vitro wounding. HGF-triggered migration involves Factin cytoskeleton reorganization, which is also evidenced by activation of Rac1. Furthermore, HGF causes ZO-1 translocation from cell-cell contact sites to cytoplasm and its concomitant activation by phosphorylation. However, no loss of expression of cell-cell adhesion proteins, including E-cadherin, ZO-1 and Occludin-1, is observed. Additionally, migration does not lead to cell dispersal but to a characteristic organized pattern in rows, in turn associated with Golgi compaction, providing strong evidence of a morphogenic collective migration. Besides migration, HGF increases oval cell invasion through extracellular matrix, process that requires PI3K activation and is at least partly mediated by expression and activation of metalloproteases. Altogether, our findings provide novel insights into the cellular and molecular mechanisms mediating the essential role of HGF/c-Met signaling during oval cell-mediated mouse liver regeneration.


Item Type:Article
Uncontrolled Keywords:C-Met, Liver progenitor cell, Migration, Invasion, Epithelial-mesenchymal transition, PI3K
Subjects:Medical sciences > Pharmacy > Biochemistry
ID Code:32438
Deposited On:27 Jul 2015 08:15
Last Modified:14 May 2016 23:01

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