title: 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.
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.
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Suárez-Causado
authors.affiliation: 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.
authors.forename: D
authors.initials: D
authors.lastname: Caballero-Díaz
authors.affiliation: 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.
authors.forename: E
authors.initials: E
authors.lastname: Bertrán
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: Roncero
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Addante
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: García-Álvaro
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Fernández
authors.affiliation: 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.
authors.forename: B
authors.initials: B
authors.lastname: Herrera
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Porras
authors.affiliation: 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.
authors.forename: I
authors.initials: I
authors.lastname: Fabregat
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Sánchez
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D015820:Cadherins; C553307:HGF protein, mouse; D009479:Neuropeptides; D062793:Occludin; C568986:Ocln protein, mouse; C484602:Rac1 protein, mouse; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D020830:rac1 GTP-Binding Protein
keywords: Epithelial–mesenchymal transition; Invasion; Liver progenitor cell; Migration; PI3K; c-Met