Ha-ras induction of the invasive phenotype results in up-regulation of epidermal growth factor receptors and altered responsiveness to epidermal growth factor in human papillary transitional cell carcinoma cells.
Recent studies have shown that orthotopic (transurethral) transplantation of human bladder cancer cell lines into nude mice permits tumor growth that more accurately reflects their clinical malignant status in the original host. We have previously demonstrated that transfection and overexpression of normal or mutated c-Ha-ras genes into a noninvasive human papillary transitional cell carcinoma cell line confer upon these cells an invasive phenotype in vivo with behavior remarkably similar to the clinical behavior of high grade bladder carcinomas. Since elevated expression levels of the epidermal growth factor receptor (EGF-R), in addition to that of c-Ha-ras, have been correlated with transitional cell carcinoma progression, we sought to determine whether up-regulation of the EGF-R had occurred in the invasive high ras expressors and if so, what functional significance this might have. Our results show that invasive cell lines which overexpress the c-Ha-ras gene also have increased epidermal EGF-R expression. This was found to occur at both the protein and mRNA levels, and analysis of the EGF-R promoter/enhancer sequences has revealed a putative AP-1 site which may possibly enhancer sequences has revealed a putative AP-1 site which may possibly serve as a ras response element. In addition, we found that the cells overexpressing the EGF-R had acquired a positive sensitivity to the stimulatory mitogenic effects of EGF. Hence, the results obtained suggest a role for either a normal or a mutated overexpressing Ha-ras in up-regulating the surface EGF-R, possibly through an AP-1 site during human bladder carcinoma progression; they also highlight the potential that EGF may have in cooperating with this EGF-R up-regulation to help mediate enhanced tumor growth.
Theodorescu
D
D
Department of Surgery, University of Toronto, Ontario, Canada.
Cornil
I
I
Sheehan
C
C
Man
M S
MS
Kerbel
R S
RS
D015152:Blotting, Northern; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D011905:Genes, ras; D006801:Humans; D009361:Neoplasm Invasiveness; D010641:Phenotype; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology
D012334:RNA, Neoplasm; D004815:Epidermal Growth Factor; D066246:ErbB Receptors