ERK2 is essential for the growth of human epithelioid malignant mesotheliomas
Corresponding Author
Arti Shukla
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Tel.: +802-656-8253, Fax: +802-656-8892
Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405-0068, USASearch for more papers by this authorJedd M. Hillegass
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorMaximilian B. MacPherson
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorStacie L. Beuschel
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorPamela M. Vacek
Department of Medical Biostatistics, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorKelly J. Butnor
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorHarvey I. Pass
Department of Cardiothoracic Surgery, NYU School of Medicine, New York, NY
Search for more papers by this authorMichele Carbone
Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI
Search for more papers by this authorJoseph R. Testa
Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA
Search for more papers by this authorNicholas H. Heintz
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorBrooke T. Mossman
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorCorresponding Author
Arti Shukla
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Tel.: +802-656-8253, Fax: +802-656-8892
Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405-0068, USASearch for more papers by this authorJedd M. Hillegass
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorMaximilian B. MacPherson
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorStacie L. Beuschel
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorPamela M. Vacek
Department of Medical Biostatistics, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorKelly J. Butnor
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorHarvey I. Pass
Department of Cardiothoracic Surgery, NYU School of Medicine, New York, NY
Search for more papers by this authorMichele Carbone
Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI
Search for more papers by this authorJoseph R. Testa
Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA
Search for more papers by this authorNicholas H. Heintz
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorBrooke T. Mossman
Department of Pathology, University of Vermont College of Medicine, Burlington, VT
Search for more papers by this authorAbstract
Members of the extracellular signal-regulated kinase (ERK) family may have distinct roles in the development of cell injury and repair, differentiation and carcinogenesis. Here, we show, using a synthetic small-molecule MEK1/2 inhibitor (U0126) and RNA silencing of ERK1 and 2, comparatively, that ERK2 is critical to transformation and homeostasis of human epithelioid malignant mesotheliomas (MMs), asbestos-induced tumors with a poor prognosis. Although MM cell (HMESO) lines stably transfected with shERK1 or shERK2 both exhibited significant decreases in cell proliferation in vitro, injection of shERK2 cells, and not shERK1 cells, into immunocompromised severe combined immunodeficiency (SCID) mice showed significant attenuated tumor growth in comparison to shControl (shCon) cells. Inhibition of migration, invasion and colony formation occurred in shERK2 MM cells in vitro, suggesting multiple roles of ERK2 in neoplasia. Microarray and quantitative real-time PCR analyses revealed gene expression that was significantly increased (CASP1, TRAF1 and FAS) or decreased (SEMA3E, RPS6KA2, EGF and BCL2L1) in shERK2-transfected MM cells in contrast to shCon-transfected MM cells. Most striking decreases were observed in mRNA levels of Semaphorin 3 (SEMA3E), a candidate tumor suppressor gene linked to inhibition of angiogenesis. These studies demonstrate a key role of ERK2 in novel gene expression critical to the development of epithelioid MMs. After injection of sarcomatoid human MM (PPMMill) cells into SCID mice, both shERK1 and shERK2 lines showed significant decreased tumor growth, suggesting heterogeneous effects of ERKs in individual MMs.
Supporting Information
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