American Journal of Respiratory Cell and Molecular Biology. 2007 Sep 13; [Epub ahead of print] [Link]
Ramos-Nino ME, Blumen SR, Sabo-Attwood T, Pass H, Carbone M, Testa J, Altomare DA, Mossman BT.
Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA.
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 3 of 7 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, LY29004. HGF-dependent phosphorylation and Fra-1 expression were decreased after knockdown of Fra-1 whereas overexpression of Fra-1 blocked the expression of MEK5 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 the 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.