title: HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway.
abstract: The ligand hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase, c-Met, are highly expressed in most human malignant mesotheliomas (MMs) and may contribute to their increased growth and viability. Based upon our observation that RNA silencing of fos-related antigen 1 (Fra-1) inhibited c-met expression in rat mesotheliomas (1), we hypothesized that Fra-1 was a key player in HGF-induced proliferation in human MMs. In three of seven human MM lines evaluated, HGF increased Fra-1 levels and phosphorylation of both extracellular signal-regulated kinase 5 (ERK5) and AKT that were inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY290042. HGF-dependent phosphorylation and Fra-1 expression were decreased after knockdown of Fra-1, whereas overexpression of Fra-1 blocked the expression of mitogen/extracellular signal-regulated kinase kinases (MEK)5 at the mRNA and protein levels. Stable MM cell lines using a dnMEK5 showed that basal Fra-1 levels were increased in comparison to empty vector control lines. HGF also caused increased MM cell viability and proliferating cell nuclear antigen (PCNA) expression that were abolished by knockdown of MEK5 or Fra-1. Data suggest that HGF-induced effects in some MM cells are mediated via activation of a novel PI3K/ERK5/Fra-1 feedback pathway that might explain tumor-specific effects of c-Met inhibitors on MM and other tumors.
authors.affiliation: University of Vermont College of Medicine, Department of Pathology, 89 Beaumont Avenue HSRF#216, Burlington, VT 05405, USA. Maria.Ramos@uvm.edu
authors.forename: Maria E
authors.initials: ME
authors.lastname: Ramos-Nino
authors.forename: Steven R
authors.initials: SR
authors.lastname: Blumen
authors.forename: Tara
authors.initials: T
authors.lastname: Sabo-Attwood
authors.forename: Harvey
authors.initials: H
authors.lastname: Pass
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Altomare
authors.forename: Brooke T
authors.initials: BT
authors.lastname: Mossman
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D048671:MAP Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D008654:Mesothelioma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1
chemical_list: D017228:Hepatocyte Growth Factor; D048671:MAP Kinase Kinase 5; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1; C482563:MAP2K5 protein, human