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Biochim Biophys Acta. 2015 Oct;1853(10 Pt A):2453-63. doi: 10.1016/j.bbamcr.2015.05.017. Epub 2015 May 20.

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.

Author information

1
Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. Electronic address: asuarezc1@unicartagena.edu.co.
2
Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. Electronic address: dcaballero@idibell.cat.
3
Laboratori d'Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain. Electronic address: ebertran@idibell.cat.
4
Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. Electronic address: ceronce@ucm.es.
5
Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. Electronic address: aaddante@ucm.es.
6
Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. Electronic address: mariagarciaalvaro@gmail.com.
7
Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. Electronic address: margafdz@ucm.es.
8
Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. Electronic address: blancamh@ucm.es.
9
Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. Electronic address: maporras@ucm.es.
10
Laboratori d'Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Departament de Ciències Fisiològiques II, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain. Electronic address: ifabregat@idibell.cat.
11
Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. Electronic address: munozas@ucm.es.

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 F-actin 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, a 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.

KEYWORDS:

Epithelial–mesenchymal transition; Invasion; Liver progenitor cell; Migration; PI3K; c-Met

PMID:
26001768
DOI:
10.1016/j.bbamcr.2015.05.017
[Indexed for MEDLINE]
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