Mutated p53 protein expression and proliferative activity in advanced gastric cancer.
OBJECTIVE
When the DNA of cells is damaged, wild-type p53 protein induces the expression of p21 (Waf1/Cip1/Sdi1), and regulates the progression of the cell cycle by inducing G1 arrest. Thus, wild type p53 or p21 protein negatively regulates cancer cell proliferation. However, in tumor with loss of expression of functional wild-type p53 protein by mutation or allelic deletion of the gene for p53, whether the proliferative activity of cancer cells might be accelerated or not is unclear. In this study, we investigated the correlation between the level of expression of mutated p53 protein and the proliferative activity of cancer cells in advanced gastric cancer.


METHODS
Ninety-seven samples from patients with gastric cancer that had invaded the serosa without lymph node metastasis (t3, n0, stage II) were investigated by immunohistochemical staining with a monoclonal antibody against p53 and against p21, and with the monoclonal antibody Ki-67. DNA ploidy patterns were analyzed by flow cytometry. The immunoreactivity against p53 and the proliferative activity of cancer cells were scored in terms of a labeling index (LI; percentage of immunostained cells) in each case. Moreover, the prognostic values for 93 surviving patients were evaluated by univariate and multivariate analysis.


RESULTS
The mean p53 LI was 24% (range: 0-82.4%) and the mean Ki-67 LI was 23.1% (range: 0-70.7%) in 97 tumors. The expression of p21 protein was detected in 30 of 97 tumors (30.9%) and DNA aneuploidy was detected in 36 of 97 tumors (37.1%). There was significant correlation between the p53 LI and the Ki-67 LI (r = 0.61, t = 7.456, p < 0.001) in 97 tumors. Although, no significant difference was detected, the mean p53 LI (18.3%) of 30 tumors with expression of p21 protein was lower than that of 67 tumors without expression of p21 protein (26.6%, p = 0.096). However, no significant correlation between expression of p21 protein and Ki-67 LI was observed. The p53 LI was not an independent prognostic factor in 93 surviving patients by multivariate survival analysis (p = 0.069). However, the 5-year survival rate of 50 patients with a low level of p53 LI (p53 LI (< or = 10%, 78.3%) was significantly better than that of 43 patients with a high level of p53 LI (p53 LI > 10%, 62.1%, p = 0.045).


CONCLUSIONS
Accumulation of mutated p53 protein might suppress the expression of p21 protein in gastric adenocarcinoma, and cancer cells with overexpression of mutated p53 protein might have a high proliferative activity.
Ikeguchi
M
M
Department of Surgery I, Faculty of Medicine, Tottori University, Yonago, Japan.
Saito
H
H
Kondo
A
A
Tsujitani
S
S
Maeta
M
M
Kaibara
N
N
D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D004791:Enzyme Inhibitors / Q000032:analysis; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D013274:Stomach Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53