Ikeguchi M, Saito H, Kondo A, Tsujitani S, Maeta M, Kaibara N
Department of Surgery I, Faculty of Medicine, Tottori University, Yonago, Japan.
Hepatogastroenterology. 1999 Jul-Aug;46(28):2648-53.
BACKGROUND/AIMS: 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.
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.
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).
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.
背景/目的：当细胞DNA受损时，野生型p53蛋白可诱导p21（Waf1/Cip1/Sdi1）表达，并通过诱导G1期阻滞来调控细胞周期进程。因此，野生型p53或p21蛋白对癌细胞增殖起负调控作用。然而，在因p53基因的突变或等位基因缺失而导致功能性野生型p53蛋白表达缺失的肿瘤中，癌细胞的增殖活性是否会加快尚不清楚。在本研究中，我们调查了晚期胃癌中突变型p53蛋白表达水平与癌细胞增殖活性之间的相关性。
采用抗p53和抗p21单克隆抗体以及Ki-67单克隆抗体，对97例侵犯至浆膜层但无淋巴结转移（t3，n0，II期）的胃癌患者样本进行免疫组化染色。通过流式细胞术分析DNA倍体模式。根据标记指数（LI；免疫染色细胞的百分比）对每种情况下的p53免疫反应性和癌细胞增殖活性进行评分。此外，通过单因素和多因素分析评估93例存活患者的预后价值。
97例肿瘤中，p53平均LI为24%（范围：0 - 82.4%），Ki-67平均LI为23.1%（范围：0 - 70.7%）。97例肿瘤中有30例（30.9%）检测到p21蛋白表达，97例肿瘤中有36例（37.1%）检测到DNA非整倍体。97例肿瘤中p53 LI与Ki-67 LI之间存在显著相关性（r = 0.61，t = 7.456，p < 0.001）。虽然未检测到显著差异，但30例表达p21蛋白的肿瘤的平均p53 LI（18.3%）低于67例未表达p21蛋白的肿瘤（26.6%，p = 0.096）。然而，未观察到p21蛋白表达与Ki-67 LI之间存在显著相关性。多因素生存分析显示，在93例存活患者中p53 LI不是独立的预后因素（p = 0.069）。然而，50例p53 LI水平低（p53 LI（≤10%，78.3%））患者的5年生存率显著高于43例p53 LI水平高（p53 LI > 10%，62.1%，p = 0.045）患者。
突变型p53蛋白的积累可能会抑制胃腺癌中p21蛋白的表达，且突变型p53蛋白过表达的癌细胞可能具有较高的增殖活性。
