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1 Ontario Cancer Institute/Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada; and
2 Research Institute, International Medical Center of Japan, Shinjuku-ku, Tokyo, Japan
Requests for reprints: Ming-Sound Tsao, University Health Network, Department of Laboratory Medicine and Pathobiology, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Phone: (416) 946-4426; Fax: (416) 946-6579. E-mail: Ming.Tsao{at}uhn.on.ca
We have investigated the influence of Ki-ras oncogene on Met/hepatocyte growth factor (HGF) receptor signaling in human carcinoma cells. The model system used in these studies included the DLD-1 colon cancer cell line with a mutated Ki-ras allele, and the DKO-4 cell line generated from DLD-1, with its mutant Ki-ras allele inactivated by targeted disruption. These cell lines were transduced with cDNAs of either active Met receptor or dominant negative Met receptor. As compared to the DLD-1 cells, constitutive overexpression of Met receptor in this cell line (DLD-1-Met) resulted in increased tumorigenicity in SCID mice. In contrast, overexpression of Met in DKO-4 cells (DKO-4-Met) that have lost oncogenic Ras activity demonstrated suppressed tumorigenicity with respect to the parent DKO-4 cell line. Tumors formed by the DLD-1-Met cells showed increased levels of mitogen-activated protein kinase (MAPK) and lower levels of apoptosis compared to the DKO-4-Met tumors. Overexpression of the dominant negative Met receptor cDNA decreased the Met phosphorylation levels in both DLD-1 and DKO-4 cells, but only suppressed tumorigenicity in the DKO-4 cell line. In vitro, HGF stimulation of DLD-1 cells resulted in a prolonged duration of MAPK activation, while DKO-4 cells exhibited a rapid attenuation of MAPK phosphorylation. The results suggest that Ki-ras mutations and HGF signaling cooperate to enhance tumor growth by increased duration of MAPK activation and decreased apoptosis in human carcinoma cells.
Key Words: ras oncogene • hepatocyte growth factor • Met receptor tyrosine kinase • aerodigestive tract cancer • mitogen-activated protein kinase
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