R-Ras promotes tumor growth of cervical epithelial cells.
BACKGROUND
R-Ras is 55% identical to H-Ras. However, these two oncogenes seem to have different tumor-transforming potential. R-Ras induced cell transformation in fibroblasts but not in other cell types. R-Ras also reportedly induces a more invasive phenotype in breast epithelial cells through integrin activation. The authors studied the mechanisms whereby R-Ras induces a malignant phenotype.


METHODS
Dominant negative (R-Ras43N) and constitutively active (R-Ras87L) mutants of R-Ras were stably transfected into human cervical epithelium C33A cells. Transfected cells were analyzed for adhesion, cell spreading, migration, and growth in culture and in nude mice. The activity of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI 3-K) also was determined by Western blot analysis and by in vitro kinase assays.


RESULTS
R-Ras87L-transfected cells, but not R-Ras43 N-transfected cells, had a higher growth rate in nude mice and in culture compared with control cells. None of the transfected C33A cells showed an increase in cell adhesion to fibronectin or collagen I, nor did they show an increment of beta1 integrin affinity. However, cells that expressed R-Ras87L, but not cells that expressed R-Ras 43N, presented a marked increase in cell spreading and migration through collagen-coated membranes. Increases in cell proliferation, spreading, and migration induced by R-Ras87L were inhibited by the PI 3-K inhibitor LY294002. In addition, PI 3-K activity, but not ERK activity, was increased only in cells that expressed R-Ras87L.


CONCLUSIONS
These data suggest that the oncogene R-Ras promotes tumor growth of cervical epithelial cells and increases their migration potential over collagen through a pathway that involves PI 3-K.
Rincón-Arano
Héctor
H
Immunology Department, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Rosales
Ricardo
R
Mora
Nancy
N
Rodriguez-Castañeda
Armando
A
Rosales
Carlos
C
D000818:Animals; D002448:Cell Adhesion; D002453:Cell Cycle; D002455:Cell Division / Q000235:genetics*; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002584:Cervix Uteri / Q000166:cytology*; D003094:Collagen; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D005353:Fibronectins; D020558:GTP Phosphohydrolases; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D015398:Signal Transduction; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000473:pathology*; D018631:ras Proteins
D005353:Fibronectins; D015513:Oncogene Proteins; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C085929:RRAS protein, human; C513254:Rras protein, mouse; D018631:ras Proteins