Carcinogenesis, Vol 19, 73-79, Copyright © 1998 by Oxford University Press
M Okamoto, K Hattori, K Fujimoto, Y Tanaka, CL Gloosby and R Oyasu
p53 mutation is commonly associated with high-grade, high-stage human
urothelial carcinomas. Recent studies suggest that p53 mutation in low-
grade, low-stage bladder carcinomas may be correlated with the progression
of the disease. In the present study, we used antisense RNA methodology in
vitro to evaluate the significance of the loss of p53 function at an early
stage of urinary bladder carcinogenesis. An immortalized nontumorigenic rat
urothelial cell line (MYP3) that strongly expresses wild-type (WT) p53 was
transfected with a plasmid (pcDL-SR alpha-296) containing a rat WT p53 cDNA
in antisense orientation. The transfection resulted in a significant
reduction in p53 mRNA expression and protein synthesis, in stimulation of
anchorage- dependent growth, and in acquisition of anchorage-independent
growth potential. Three such clones, when tested in athymic nude mice, all
formed muscle-invasive, high-grade transitional cell carcinomas at s.c.
injection sites. When cells were inoculated into an orthotopic site
(urinary bladder), one of two antisense transfectants tested formed bulky
tumors in the bladder in all seven nude mice and metastases to lungs in
three of the seven mice. Analysis of these cells revealed a decrease in the
expression of p21 (WAF1, sdi1, or CIP1) and retinoblastoma (Rb) gene
product. Phosphorylation of Rb protein was not inhibited when the cells
were starved. No significant difference was observed in the expression of
p16 protein. In cell cycle analysis, all antisense transfectants tested
escaped from G1 arrest by starvation. Furthermore, secretion of interleukin
(IL)-6 into culture medium was increased significantly. Treatment with
anti-IL-6 antibody suppressed anchorage-dependent growth. This study
directly demonstrates that the loss of p53 function at an early stage of
urothelial carcinogenesis may result in acquisition of a malignant
phenotype by regulating IL-6 production as well as cell cycle related
genes.
ARTICLES
Antisense RNA-mediated reduction of p53 induces malignant phenotype in nontumorigenic rat urothelial cells
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
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