p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells.
Dominant negative (DN) mutations of tumor suppressor p53 (TP53) are clinically associated with cancer progression and metastasis of endometrial malignancy. To investigate the DN effect on tumor migration and invasion, we generated cells that stably co-expressed wild-type (wt) and R273H DN mutant TP53 (273H cells), and wt and R213Q recessive mutant TP53 (213Q cells), by transfection in endometrial cancer cells HHUA that expressed wt p53. R273H, but not R213Q, repressed wt p53-stimulated transcription of p21, Bax, and MDM2. 273H cells also showed markedly increased in vitro invasion and migration potentials, and displayed reduced Maspin, PAI-1, and KAI1 mRNA expressions as compared with 213Q and wt cells. The induction of wt p53 function by use of Adriamycin resulted in the inhibition of the invasion/migration capacity in association with the up-regulation of p53 target genes to a far greater degree in 213Q and wt cells than in 273H cells. R273H expression in p53-null cancer cell SK-OV-3 and Saos-2 did not significantly affect cell invasion and migration activities. Taken together, these results suggest that transdominance of R273H mutant over wt p53 rather than a gain-of-function promotes tumor metastasis by increasing invasion and migration in HHUA cells.
Dong
Peixin
P
Department of Gynecology, Hokkaido University Graduate School of Medicine and School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
Tada
Mitsuhiro
M
Hamada
Jun-Ichi
J
Nakamura
Akihiro
A
Moriuchi
Tetsuya
T
Sakuragi
Noriaki
N
D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D016889:Endometrial Neoplasms / Q000235:genetics / Q000473:pathology*; D005260:Female; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection
D017931:DNA Primers