p53和p21WAF1/CIP1基因在上皮性卵巢癌中的表达及临床意义

目的探讨联合检测p53和p21蛋白表达与上皮性卵巢癌预后的关系.方法 108例上皮性卵巢癌标本用于研究,每个标本同时用免疫组化的方法检测p53和p21蛋白表达.结果 p53(－)和p53( )患者的5年生存率分别为60.47%和29.43%,差异有显著性(P=0.0228).p21(－)和p21( )患者的5年生存率分别为31.58%和47.14%,差异有显著性(P=0.0246).p53(－)而p21( )患者的预后明显优于其他患者(P=0.0013).多因素分析显示p53、p21蛋白联合表达状态是判断上皮性卵巢癌预后的独立因子. 53蛋白表达与p21蛋白表达呈负相关(P=0.0003).结论联合检测p53、p21蛋白表达在判断上皮性卵巢癌预后上的意义优于单纯检测p53或p21蛋白表达,对临床有指导意义.     

p53和p21WAF1蛋白在肝细胞肝癌中表达的意义

 【摘要】　目的　探讨p53和p21WAF1蛋白在肝细胞肝癌（HCC）中的表达及其意义。方法　应用免疫组织化学SP法检测41例HCC及相应30例癌旁肝组织中p53和p21WAF1蛋白的表达。结果　p53和p21WAF1蛋白在HCC中阳性表达率分别为43.9 ％和75.6 ％，明显高于癌旁组织，差异有统计学意义（P＜0.01）。HCC中p53蛋白表达与p21WAF1蛋白表达无明显相关性（P＞0.05）。p53蛋白表达在不同组织学分级、有无肝内或门静脉转移之间差异有统计学意义，而p21WAF1蛋白表达在不同临床病理特征间差异无统计学意义。结论　p53和p21WAF1蛋白高表达均在HCC发生、发展中起作用，但两者间并无相关性。p21WAF1的诱导存在着不依赖p53的途径。     

胃癌中p21WAF1与p53基因的相关性研究

目的　探讨胃癌中 p2 1WAF 1与 p5 3基因的关系。方法　采用 S- P法检测 p2 1WAF 1和 p5 3在胃癌中的表达。结果　 p2 1与 p5 3在正常胃黏膜、不典型增生、胃癌中的阳性表达率分别为 10 0 .0 %与 0 %、92 .5 %与 15 .0 %、39.8%与 5 6 .5 % ;40例不典型增生 ,p5 3阳性而 p2 1阴性者为 5 .0 % ,p5 3阴性而 p2 1阳性为 82 .5 % (P<0 .0 5 ) ;p2 1、p5 3阳性高分化腺癌各为 6 3.3%与 36 .7% ,与低分化腺癌 32 .7%与 78.2 %比较 ,差异有显著性 (P<0 .0 5 ) ;48.1%的胃癌 p2 1、p5 3蛋白表达相反 (P>0 .0 5 ) ;p2 1表达在侵犯浅肌层为 6 0 .0 %显著高于深肌层的 35 .2 % (P<0 .0 5 ) ;p2 1、p5 3在原发与转移癌中一致表达为 35 .3%与 70 .6 % ,皆与未转移癌 6 2 .5 %与 42 .5 %有显著性差异 (P<0 .0 5 ) ;p2 1在 TNM 期 6 0 .0 %、 期 5 6 .2 %显著高于 期 2 7.8%、 期 2 2 .2 % (P<0 .0 5 )。结论　正常胃黏膜和不典型增生 p2 1蛋白表达大部分依赖 p5 3蛋白 ,而胃癌在相当程度上不依赖。p2 1失表达和 p5 3异常表达与胃癌发生、分化程度、转移有关 ,而 p2 1失表达还与侵袭、临床分期关系密切     

Relations between immunologically different p53 forms,p21(WAF1) and PCNA expression in ovarian carcinomas

The role of tumor suppressor p21WAF1 expression in epithelial ovarian cancer has not been definitely explained and the clarification of mutual p53 and p21WAF1 relations considering proliferative activity seems to be very important for understanding of a functional link between p53 and cell-cycle control. Therefore the expression of p53 and p21WAF1 was assessed immunohistochemically in a series of 50 ovarian carcinomas considering clinicopathological variables. The reactivity of three anti-p53 monoclonal antibodies (DO-7, PAb240, PAb1620) recognizing immunologically distinct forms of p53 were analysed in relation to p21WAF1 level in individual patients. p21WAF1 was expressed in 24 (48%) of all cases. The detection of p53 protein was related to the antibody applied and DO-7 antibody appears to be better than both PAb240 and PAb1620. However, independently of antibody used significant inter- and intratumoral heterogeneity in p53 and p21WAF1 expression was revealed. The identification of different p53/p21WAF1 phenotypes reflect the complex and multiple relations between these two cell-cycle regulators indicating that in ovarian carcinomas p21WAF1 activation may be both p53-dependent and p53-independent. High cell proliferation was usually accompanied by undetectable or weak p21WAF1 staining. There was no significant correlation between p53 and p21WAF1 expression and histology, stage and grade of ovarian carcinomas (p>0.05).     

原发性肝细胞癌组织中p53和p21WAF/CIP1及MDM2蛋白的表达及其临床意义

目的探讨p53、p21WAF/CIP1及MDM2蛋白在原发性肝细胞癌(hepatocellular carcinoma, HCC)组织中的表达及其临床病理意义.方法选取115例HCC及其相应的癌旁肝组织构建组织芯片,应用免疫组织化学方法检测p53、p21WAF/CIP1及MDM2蛋白的表达,采用统计学分析它们的表达及其与临床病理参数之间的关系.结果p53、p21WAF/CIP1及MDM2在HCC组织中的阳性表达率分别为83.5%(96/115)、36.5%(42/115)和48.7%(56/115),同癌旁组织相比,p53、p21WAF/CIP1及MDM2的表达均明显增高,P＜0.05.两两相关分析比较, p53表达分别与p21WAF/CIP1和MDM2表达有关;p53、p21WAF/CIP1及MDM2的阳性表达率与患者性别、年龄、肿瘤大小、肿瘤数量、HBsAg、病理分级、血清AFP浓度和患者生存时间均无关,P均＞0.05.结论p53、p21WAF/CIP1及MDM2在HCC组织中呈增高表达并具有一定的相关性,提示它们可能在HCC的发生发展中发挥重要的作用.     

Endogenous p21WAF1/CIP1 status predicts the response of human tumor cells to wild-type p53 and p21WAF1/CIP1 overexpression

Expression of exogenous wild-type (wt) p53 protein can suppress the growth and/or induce apoptosis in different tumor cells. The effect of exogenous p21(WAF1/CIP1) expression is more controversial: while it can induce apoptosis in some cells, it can protect against p53-mediated apoptosis in others. We used adenoviral vectors to introduce p53 and p21(WAF1/CIP1) genes into human tumor cell lines with different p53 and/or p21(WAF1/CIP1) status. The cell growth inhibition and the induction of apoptosis were measured. Overexpression of wt p53 induced more efficient growth inhibition and apoptosis in SW 620 (mutant p53) and HeLa (inactivated p53 protein) than in MCF-7 (wt p53) and CaCo-2 cell line, which was the most resistant to p53 overexpression despite the p53 mutation. Unlike HeLa and SW 620 cells, the basal p21 protein level was readily detected in CaCo-2 and MCF-7 cells. Overexpression of p21(WAF1/CIP1) gene induced somewhat less pronounced growth inhibition of all cell lines tested, but it also induced apoptosis in HeLa and SW 620 cells. These results suggest that the basal, but not the inducible, levels of p21(WAF1/CIP1) protein in tumor cells could protect from p53-mediated apoptosis. On the other hand, overexpression of p21(WAF1/CIP1) gene itself can induce apoptosis in cells with no basal p21(WAF1/CIP1) protein level. Possible mechanisms of the differential response to these genes are discussed.     

Reduced p21(WAF1/CIP1) protein expression is predominantly related to altered p53 in hepatocellular carcinomas

To investigate the relationship between the expression of p21(WAF1/CIP1) protein and p53 status and the possible role of the two proteins in hepatocellular carcinomas (HCCs), we examined the expression of p21(WAF1/CIP1) and p53 immunohistochemically in 81 tumours from 65 patients with hepatocellular carcinoma. p21(WAF1/CIP1) protein was absent from 59 of 81 tumours (72.8%), and altered p53 expression was found in 43 (53.1%). p21(WAF1/CIP1) expression was significantly associated with p53 status (P = 0.0008); 38 of 59 tumours lacking p21(WAF1/CIP1) protein were accompanied by altered p53 expression. Further analyses showed that p21(WAF1/CIP1) expression was inversely correlated with p53 expression in hepatitis C virus (HCV)-related HCCs, but not in HBV-related hepatocellular carcinomas and hepatocellular carcinomas without viral infection. All 11 tumours with intrahepatic metastasis showed altered p21(WAF1/CIP1) or p53 expression. In contrast, no intrahepatic metastasis was found in any of the 17 tumours without abnormal expression of either of the two proteins. These results suggest that: (1) different modes of p21(WAF1/CIP1) regulation are involved in HCCs differing in their hepatitis viral infection status, and p21(WAF1/CIP1) expression appears to be predominantly related to altered p53 in HCV-related HCCs; (2) disruption of the p53-p21(WAF1/CIP1) cell-cycle-regulating pathway may contribute to malignant progression of HCC.     

抑癌基因ING1、p21/WAF1、P53蛋白在胃癌中的表达

目的　研究ING1、p2 1 /WAF1、p53基因蛋白在胃癌组织中的表达意义及相互关系。方法　对 71例胃癌组织应用Envision免疫组化法 ,检测 p33ING1 、p2 1 /WAF1、p53的表达情况 ,分析其相关性 ,结合临床病理因素 ,探讨胃癌发生、进展及预后的关系。结果　p33ING1 与p2 1 /WAF1、p53表达有相关性 (P <0 .0 5) ,p33ING1 表达率为 62 .0 % (44/71 ) ,与正常组织相比呈低表达 ,与胃癌的浸润、淋巴结转移、远隔转移、分化程度有相关性 (P <0 .0 1 ) ;p2 1 /WAF1表达率为54 .9% (39/71 ) ,与胃癌浸润相关 (P <0 .0 5) ;p53表达为 63 .4 % (45/71 ) ,与浸润及淋巴结转移相关 (P <0 .0 1 )。结论　ING1是抑癌基因 ,其蛋白p33ING1 在胃癌中低表达 ,对胃癌的发生、发展可能起重要作用 ,p33ING1 、p2 1 /WAF1、p53表达可作为判断胃癌恶性程度及预后的重要指标     

胃癌中p21WAF1/CIP1、细胞周期素D1、p53表达的相关性

目的　探讨p2 1WAF1/CIP1、细胞周期素D1(cyclinD1)、p5 3在胃癌中表达之间的相关性。 方法　应用原位杂交技术检测p2 1WAF1/CIP1mRNA、细胞周期素D1mRNA及免疫组化技术检测p5 3蛋白在胃癌中的表达。结果　p2 1WAF1/CIP1mRNA在癌组织及癌旁正常粘膜中阳性表达率各为 93.15 % (6 8/73)及76 .71% (5 6 /73) ,二者相比具有显著差异 (P <0 .0 5 )。CyclinD1mRNA在癌组织及癌旁正常粘膜中阳性表达率各为 5 4 .79% (40 /73)及 30 .16 % (2 2 /73) ,二者具有显著差异 (P <0 .0 5 )。p5 3蛋白在胃癌中的阳性表达率为 32 .87% (2 4 /73) ,p5 3过表达者 ,其 p2 1WAF1/CIP1mRNA表达较p5 3阴性者为低 ,二者存在显著差异 (P <0 .0 5 )。p2 1WAF1/CIP1表达与细胞周期素D1表达呈负相关。结论　p2 1WAF1/CIP1、CyclinD1、p5 3的异常表达及它们之间可能存在的相互作用 ,对于胃癌的发生发展具有重要意义。     

Clinical and pathological associations with p53 tumour-suppressor gene mutations and expression of p21WAF1/Cip1 in colorectal carcinoma.

Inactivation of the p53 tumour-suppressor gene is common in a wide variety of human neoplasms. In the majority of cases, single point mutations in the protein-encoding sequence of p53 lead to positive immunohistochemistry (IHC) for the p53 protein, and are accompanied by loss of the wild-type allele. Recently, the WAF1/Cip1 gene was identified as one of the genes induced by wild-type p53, and increased expression of p21WAF1/Cip1 has been found to reflect the status of the p53 tumour-suppressor pathway. We investigated the inactivation of p53 in a relatively small, but well-characterised, group of 46 colorectal carcinomas that were previously studied for allelic alterations, ras oncogene mutations and DNA aneuploidy. Alterations in p53 were identified by IHC, loss of 17p and DNA sequence analysis of exons 5-8, whereas p21WAF1/Cip1 protein expression was determined by IHC. p53 mutations were identified in 19 of the 46 tumours (41%), whereas positive IHC for p53 was found in 21 of the 46 tumours (46%). Positive IHC for p21WAF1/Cip1 was detected in 16 of 42 cases (38%). We found no relationship between p21WAF1/Cip1 staining and p53 protein expression or p53 mutational status. Inactivating mutations in the p53 gene correlated with LOH at 17p but not with LOH at 5q or 18q, Dukes'' stage, tumour grade or DNA ploidy. There was a higher survival rate independent of Dukes'' stage in the group with no alterations in p53 compared with those with evidence of dysfunction of p53, but the difference was not statistically significant. We conclude that inactivation of p53 and altered expression of p21WAF1/Cip1 are common in colorectal carcinoma but do not correlate with each other or with the clinical or pathological parameters investigated.     

Correlation between reduced p21(WAF1/CIP1) expression and abnormal p53 expression in esophageal carcinomas

Direct gene transfer into somatic tissue iii vivo is a developing technology with potential application for cancer gene therapy. In this study, recombinant vaccinia virus encoding human IL-2 gene (rVV-IL-2) was used as a candidate vector in mediating iii vivo gene therapy. After rVV-IL-2 was expanded in VERO cells for 72 h, high titer (10(8)-10(10) PFU/ml) rVV-IL-2 were harvested. When 10(6) murine melanoma cells (F16-F10) were infected with rVV-IL-2, about 200 U/ml IL-2 activity was detected in the supernatants at 8 h, and the up-regulation of ICAM-1 and MHC-I expressions on the melanoma cells were observed. The treatment of murine melanoma model by local injection of rVV-IL-2 into the tumor site showed that rVV-IL-2 transfection significantly inhibited the tumor growth and prolonged the survival time of tumor-bearing mice. The splenocytes from rVV-IL-2 treated mice showed higher cytotoxicities of NK, LAK and CTL in comparison with those from the controls. These results suggest that in vivo transfection mediated by rVV-IL-2 has potential effectiveness in enhancing host immunity and would be a useful approach to cancer gene therapy.     

Apigenin induces cell cycle arrest and p21/WAF1 expression in a p53-independent pathway

Apigenin, a common dietary flavonoid, has been shown to induce cell growth-inhibition and cell cycle arrest in many cancer cell lines. One important effect of apigenin is to increase the stability of the tumor suppressor p53 in normal cells. Therefore, apigenin is expected to play a large role in cancer prevention by modifying the effects of p53 protein. However, the mechanisms of apigenin's effects on p53-mutant cancer cells have not been revealed yet. We assessed the influence of apigenin on cell growth and the cell cycle in p53-mutant cell lines. Treatment with apigenin resulted in growth-inhibition and G2/M phase arrest in two p53-mutant cancer cell lines, HT-29 and MG63. These effects were associated with a marked increase in the protein expression of p21/WAF1. We have shown that p21/WAF1 mRNA expression was also markedly increased by treatment with apigenin in a dose- and time-dependent manner. However, we could not detect p21/WAF1 promoter activity following treatment with apigenin. Similarly, promoter activity from pG13-Luc, a p53-responsive promoter plasmid, was not activated by treatment with apigenin with or without p53 protein expression. These results suggest that there is a p53-independent pathway for apigenin in p53-mutant cell lines, which induces p21/WAF1 expression and growth-inhibition. Apigenin may be a useful chemopreventive agent not only in wild-type p53 status, but also in cancer with mutant p53.     

p21/WAF1 expression as related to p53, cell proliferation and prognosis in epithelial ovarian cancer

The role and prognostic value of the tumour suppressor p21/WAF1 expression in epithelial ovarian cancer has not yet been defined. Therefore, the expression of p21/WAF1 was assessed immunohistochemically (IHC) in 316 epithelial ovarian malignancies in relation to p53, cell proliferation and patient survival. p21/WAF1 expression was inversely correlated with p53 and cell proliferation. Low p21/WAF1 expression was significantly associated with high grade of the tumour (P = 0.0005), advanced FIGO stage (P = 0.001) and primary residual tumour (P = 0.0001). Low p21/WAF1 expression was a marker of poor overall survival (P = 0.012). Similarly, p53-positivity and high cell proliferative activity were significant predictors of poor survival in univariate analyses. Moreover, the patients with p21-/p53+ tumours had a poorer overall (P < 0.00005) and recurrence-free (P = 0.0005) survival in univariate analyses, and the p21/p53 expression independently predicted tumour recurrence in Cox's multivariate analysis. Our results suggest that p21/WAF1 expression is mostly p53-dependent in epithelial ovarian cancer. High p21/WAF1 expression seems to function as a negative cell cycle regulator and as a marker of favourable disease outcome in epithelial ovarian cancer. In addition, the patients with their tumour expressing no or low p21/WAF1 protein but positive for p53 had a notably higher risk of recurrent disease, implicating that these patients might be more prone to treatment failures.     

p21WAF1 immunohistochemical expression in breast carcinoma: correlations with clinicopathological data, oestrogen receptor status, MIB1 expression, p53 gene and protein alterations and relapse-free survival.

p21 protein (p21) inhibitor of cyclin-dependent kinases is a critical downstream effector in the p53-specific pathway of growth control. p21 can also be induced by p53-independent pathways in relation to terminal differentiation. We investigated p21 immunoreactivity in normal breast and in 91 breast carcinomas [three in situ ductal carcinomas (DCIS) with microinfiltration and 88 infiltrating carcinomas, 17 of which with an associated DCIS; 57 node negative and 34 node positive] with long-term follow-up (median = 58 months). Seven additional breast carcinomas with known p53 gene mutations were investigated. In normal breast p21 expression was seen in the nuclei of rare luminal cells of acinar structures, and in occasional myoepithelial cells. Poorly differentiated DCIS showed high p21 expression, whereas well-differentiated DCIS tumours showed few p21-reactive cells. p21 was seen in 82 (90%) infiltrating tumours; staining was heterogeneous; the percentage of reactive nuclei ranged from 1% to 35%. High p21 expression (more than 10% of reactive cells) was seen in 24 (26%) cases, and was associated with high tumour grade (P = 0.032); no associations were seen with tumour size, metastases, oestrogen receptor status, MIB1 expression and p53 expression. p21 expression in cases with p53 gene mutations was low in six cases and high in one. High p21 expression was associated with short relapse-free survival (P = 0.003).     

鼻咽癌组织中p21／WAF1和PCNA的表达

目的:探讨鼻咽癌组织中p21/WAF1和PCNA表达异常的意义。方法:采用免疫组织化学(S--P)方法和显微摄象计算机图像分析技术。结果:55例鼻咽癌组织中p21/WAF1阳性32例(58.2％),PI=62.32±13.647。结论。提示p21/WAF1的低表达和PCNA的过表达在鼻咽癌细胞增殖和转移过程中起重要作用。     

Disruption of p53-p21/WAF1 cell cycle pathway contributes to progression and worse clinical outcome of hepatocellular carcinoma

p53-p21/WAF1 cell cycle pathway plays an important role in growth control, and the inappropriate deregulation of this pathway has been implicated in carcinogenesis. Although the role of p53 in hepatocellular carcinoma (HCC) has been suggested, its exact molecular mechanism in relation to its down-stream gene p21/WAF1 remains unclear. To investigate the relationship between the expression of p53 and p21/WAF1 and the possible roles of the 2 proteins in HCC, we examined the intracellular expression of p53, p21/WAF1 and PCNA immunohistochemically, together with apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay in 35 clinical tissue specimens. The correlation between the clinicopathologic parameters and the intracellular gene expression were analyzed. The results showed that p53 over-expression is a reliable marker for mutational modulation of p53 function. p53 was negatively correlated with p21/WAF1 in hepatitis B virus-related HCC (p=0.024, r=-0.432). Patients with a high p53 expression had a significantly higher Edmondson grading (12/21 vs 13/14, p=0.024) and larger tumor size (10 vs 6 cm, p=0.029). Patients with higher p53 expression had shorter disease-free survival (4 vs 19 months, p=0.0131) and overall survival (11 vs 42 months, p=0.0031). Intracellular expression of p21/WAF1 was positively correlated to proliferating cell nuclear antigen (p=0.001, r=0.776) and apoptosis (p=0.003, r=0.639). Our findings suggest that disruption of p53-p21/WAF1 cell cycle pathways contributes to tumor progression and worse clinical outcome of HCC.     

高危人乳头状瘤病毒和p53、p21WAF1、MDM2在子宫颈鳞癌中的表达

 目的 探讨子宫颈浸润性鳞状细胞癌（ISCC）中人乳头状瘤病毒（HPV）16／18、31／33 感染及p53、p21WAF1、双微体2（MDM2）蛋白的表达，研究其相关性及在ISCC发生、发展中的作用。方法 利用组织芯片、原位杂交和免疫组织化学法检测106例ISCC、10例子宫颈上皮内瘤变（CIN）、10例正常子宫颈鳞状上皮（NCE）中HPV16／18、31／33和p53、p21WAF1、MDM2的表达。应用SPSS12.5统计软件分析结果。结果 HPV16／18、p53、p21WAF1、MDM2在ISCC中的表达明显高于CIN和NCE组，差异有统计学意义；HPV31／33表达与淋巴结转移呈正相关（P＜0.05）；p53蛋白与组织学分级、淋巴结转移呈正相关；p21WAF1阳性表达率与子宫颈管壁浸润深度呈正相关；MDM2蛋白与临床各参数均无相关性（P＞0.05）。结论 高危HPV和突变型p53在ISCC的发生、发展中起重要作用，p53的下游基因MDM2作为癌基因在进展中起作用，而p21WAF1基因可能不是单纯作为抑癌基因在起作用。     

上皮性卵巢癌组织中p21WAF1表达及其与P53和PCNA的相关性

背景与目的:近年研究表明,p21WAF1下调与多种肿瘤发生、发展有关,但其与上皮性卵巢癌的关系研究甚少,本研究从mRNA和蛋白水平探讨p21WAF1基因在上皮性卵巢癌发生发展中的作用及其与P53和PCNA蛋白表达的相关性.方法:应用RT-PCR法检测55例上皮性卵巢癌、32例良性卵巢肿瘤和30例正常卵巢组织中p21WAF1 mRNA表达,免疫组化法检测P21WAF1、P53、PCNA蛋白表达,并结合其临床病理参数及预后进行分析.结果:上皮性卵巢癌、良性卵巢肿瘤、正常卵巢组织中p21WAF1 mRNA阳性率分别为40.00%、56.25%、73.33%(P=0.012),P21WAF1蛋白阳性率分别为36.36%、56.25%、80.00%(P=0.001).上皮性卵巢癌p21WAF1 mRNA及其蛋白表达均低于其它两组,而P53、PCNA蛋白表达阳性率显著高于其它两组(P＜0.05).上皮性卵巢癌中p21WAF1 mRNA表达与其蛋白表达呈显著性正相关,与PCNA表达呈负相关,与P53表达无显著性相关.P21WAF1蛋白表达与PCNA、P53表达均呈负相关.P21WAF1蛋白低表达与卵巢癌FIGO分期晚有显著性相关(P=0.032),与患者年龄、组织学类型、病理分级、残余肿瘤大小无显著性相关(P＞0.05),而p21WAF1 mRNA与上述各项临床病理参数均无显著性相关(P＞0.05).单因素分析显示p21WAF1 mRNA与P21WAF1蛋白低表达患者预后差(P＜0.05).结论:上皮性卵巢癌组织中P21WAF1表达下调.p21WAF1基因检测结果有可能作为预测上皮性卵巢癌预后的一种参考指标.     

p21WAF1/CIP1和p53蛋白表达在胃癌发生发展过程中的研究

目的研究p21WAF1/CIP1和p53蛋白在胃癌发生发展过程中的作用及表达的临床病理意义.方法采用免疫组化SP法对正常胃粘膜、萎缩性胃炎伴肠上皮化生、萎缩性胃炎伴不典型增生组织各20例和78例胃癌组织标本进行p21WAF1/CIP1和p53蛋白检测.结果胃癌组织中p53蛋白阳性表达率高于正常胃粘膜、萎缩性胃炎伴肠上皮化生和不典型增生组(P＜0.05),而p21WAF1/CIP1蛋白阳性表达低于正常胃粘膜、萎缩性胃炎伴肠上皮化生组(P＜0.01)p21WAF1/CIP1、p53蛋白表达与胃癌的分化程度相关(P＜0.05);有淋巴结转移组p21WAF1/CIP1蛋白表达率低于无淋巴结转移组(P＜0.05),而有淋巴结转移组p53蛋白表达率高于无淋巴结转移组(P＜0.05);p53蛋白表达与胃癌浸润深度有关.结论p53蛋白高表达与p21WAF1/CIP1蛋白失表达可能参与胃癌的发生发展过程;检测p53和p21WAF1/CIP1蛋白作为反映胃癌病理学特点的参考指标可能有一定意义;p21WAF1/CIP1蛋白表达在胃癌可能存在非p53诱导表达途径.     

Dysfunction of p53 pathway in human colorectal cancer: analysis of p53 gene mutation and the expression of the p53-associated factors p14ARF, p33ING1, p21WAF1 and MDM2

Mutations of p53 tumor suppressor gene increase with tumor progression in colorectal cancers. In this study, we examined the expressions of p33ING1, p14ARF, MDM2 and p21WAF1 mRNA in 25 advanced colorectal cancers by quantitative RT-PCR method, and compared the expression levels of p33ING1, p14ARF, p21WAF1 and MDM2 in relation to p53 status in the tumors. Fifteen of 25 colorectal cancers (60%) showed abnormal accumulation of p53 protein in the nucleus, and the remaining 10 colorectal cancers (40%) were negative for p53 immunostaining. We found a G --> T transition (nonsense mutation) at the first nucleotide of codon 298 (exon 8) in one p53-negative case, and a frame shift mutation on exon 7 in another p53-negative case. In remaining eight p53-negative cases, there was no mutation in the entire open reading frame of p53 cDNA. Interestingly, in eight cases with p53 wild-type gene, 6 cases (75%) showed a marked down-regulation of p14ARF mRNA, and three cases (37.5%) over-expressed MDM2 mRNA. Only one case with wild-type p53 gene showed normal level expression of p53 regulatory-factors (p33ING1, p14ARF, and MDM2). Thus, p53 tumor suppressor pathway was disrupted in 24 of 25 colorectal cancers (96%).