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HGF Mediates Cell Proliferation of Human Mesothelioma Cells through a PI3K/MEK5/Fra-1 Pathway

¹ Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont; ² Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina; ³ Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York; ⁴ Cancer Research Center of Hawaii, Honolulu, Hawaii; and ⁵ Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Maria E. Ramos-Nino, Ph.D., University of Vermont College of Medicine, Department of Pathology, 89 Beaumont Avenue HSRF#216, Burlington, VT 05405. E-mail: Maria.Ramos{at}uvm.edu

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.

Key Words: hepatocyte growth factor/scatter factor • fos-related antigen 1 • phosphatidylinositol 3-kinase • MEK5 • mesothelioma

CLINICAL RELEVANCE Data here suggest that hepatocyte growth factor/scatter factor–-induced effects in some malignant mesothelioma (MM) cells are mediated via activation of a novel phosphatidylinositol 3-kinase/mitogen/extracellular signal–regulated kinase kinases 5/fos-related antigen 1 feedback pathway that might explain differential effects of c-Met inhibitors on MM and other tumor types.