Met receptor overexpression and oncogenic Ki-ras mutation cooperate to enhance tumorigenicity of colon cancer cells in vivo.
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.
Long
Isolde Seiden
IS
Ontario Cancer Institute/Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada.
Han
Kathy
K
Li
Ming
M
Shirasawa
Senji
S
Sasazuki
Takehiko
T
Johnston
Michael
M
Tsao
Ming-Sound
MS
D017209:Apoptosis / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D003110:Colonic Neoplasms; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt