凋亡相关基因p53、bcl-2、bax在前列腺组织中的相关性

目的　探讨细胞凋亡相关基因p53、bcl-2、bax在前列腺组织中的相关性。 方法　收集36例前列腺癌(prostate caner, PCa)、20例前列腺增生(benign prostatic hyperplasia,BPH)和11例正常前列腺(normal prostatic, NP),应用免疫组织化学S-P法检测凋亡相关基因p53、bcl-2、bax蛋白的表达。 结果　①PCa和BPH组bcl-2蛋白阳性表达率明显高于NP组（P<0.05）,而PCa组与BPH组阳性率差异无显著性。PCa组p53蛋白阳性表达率明显高于BPH组和NP组（P<0.01）,而BPH组与NP组阳性率无显著性差异（P>0.05）。②p53与PCa分级有关,随着肿瘤分级增高而呈正相关（P<0.05）;bcl-2与PCa分级有关,随着肿瘤分级增高而呈正相关（P<0.01）,显示bcl-2、p53蛋白表达随着病理分级的增高而增高。PCa、BPH和NP中bax阳性表达率差异无显著性。③p53蛋白表达阳性率≤5年生存组明显高于>5年生存组,呈负相关（P<0.05）;bcl-2、bax蛋白表达与生存期无关（P>0.05）。 结论 细胞凋亡相关基因 p53、bcl-2、bax蛋白的异常表达与PCa的发生和发展、病理分级和预后有相关性。     

p53抑癌基因与肿瘤病人的预后

正常野生型ｐ５３基因表达的蛋白具有调节细胞周期、诱导受损伤细胞凋亡的功能，ｐ５３抑癌基因与肿瘤病人预后的关系是肿瘤生物学行为研究的热点之一。通过总结近年来关于ｐ５３抑癌基因与肿瘤病人预后方面的文献，分析结论不一致或相互矛盾的原因，指出研究方法的差异，阐述了ｐ５３抑癌基因作为肿瘤病人预后因子时与经典的ＴＮＭ分期系统之间的关系，对临床实践中合理应用这一指标具有重要的参考意义     

抑癌基因p16研究进展

ｐ１６作为一个不同于ｐ５３的新发现的抑癌基因，为细胞周期与肿瘤发生机制的研究提供了新的途径，对今后肿瘤的治疗将具重要意义。对ｐ１６基因结构、定位、突变、表达情况以及作用机制作一综述     

横纹肌肉瘤中MDM2及p53基因表达的原位杂交检测

目的观察ＭＤＭ２、ｐ５３癌基因在横纹肌肉瘤（ＲＭＳ）发病中的作用及其与临床病理、预后间的关系。方法对确诊并有随访的３１例ＲＭＳ标本,用原位杂交技术进行ＭＤＭ２、ｐ５３定位观察。结果发现ＭＤＭ２及ｐ５３癌基因表达阳性率分别为７７４％（２４／３１例）和６６７％（２１／３１例）,其阳性率与年龄、性别和ＲＭＳ组织类型无明显关联（Ｐ＞０．０５）,但阳性率及其强度与ＲＭＳ分化程度（Ⅰ级与Ⅲ级）,转移与否及存活率差异有显著性（Ｐ＜０．０５）。结论ＭＤＭ２、ｐ５３阳性检出率有助于判断ＲＭＳ恶性程度及预测肿瘤的转移和预后。     

肝细胞癌p53基因与p21WAF1／CIP1基因的相关性分析

近年来，癌基因、抑癌基因在肿瘤发生发展中的作用日益受到人们的关注，不少学者进行了ｐ５３基因与肝细胞肝癌（ＨＣＣ）发生的相关性研究。有作者报道，野生型ｐ５３基因抑制细胞增殖的功能是通过ｐ２１ＷＡＦ１／ＣＩＰ１基因介导的〔１〕。本文检测７２例ＨＣＣ组织中...     

利用FISH技术检测胃癌组织中HER2基因及其与p53蛋白表达的相关性

目的 探讨胃癌组织中HER2基因状态及其与p53蛋白表达的相关性.方法 采用FISH和免疫组织化学技术对67例胃癌组织中HER2基因状态和p53蛋白进行了检测.结果 FISH检测HER2基因扩增率17.9%(12/67),HER2基因无扩增的55例中拷贝数增加和基因扩增者共49.3%(33/67).HER2蛋白表达率43.3%(29/67),在HER2蛋白表达3+、2+者中HER2基因扩增比例分别为3/4和6/9与1+者3/16比较差异有统计学意义(P<0.05).p53蛋白表达率58.2%(39/67),HER2基因扩增率、p53蛋白表达率与胃癌的浸润深度、淋巴结有无转移差异有显著性(P <0.05);与组织学类型、年龄、性别差异无统计学意义(P>0.05).结论 HER2基因扩增率和基因拷贝数增加与p53蛋白表达率呈正相关,HER2基因状态和p53蛋白表达的联合检测对于胃癌的转移、患者的病情发展及预后评估有一定的参考价值,对指导临床制定个体化治疗方案有重要意义.     

p53抑癌基因在妇科肿瘤中的研究进展

ｐ５３等位基因突变和／或丢失或者是ｐ５３蛋白失活可导致妇科肿瘤发生，ｐ５３基因在卵巢癌、子宫内膜癌中突变率较高，是卵巢癌、子宫内膜癌发生的主要原因之一，ｐ５３蛋白可作为卵巢癌、子宫内膜癌的预后指标。而宫颈癌中ｐ５３基因突变率较低，宫颈癌的发生主要是通过人乳头状瘤病毒感染导致ｐ５３蛋白失活造成的     

抑癌基因p53及蛋白产物在星形细胞瘤中的表达

抑癌基因ｐ５３及蛋白产物在星形细胞瘤中的表达郭琳琅曹长安肖莎区士欢采用核酸分子原位杂交技术和免疫组化方法观察了ｐ５３基因在３７例星形细胞瘤中的表达情况，探讨ｐ５３基因与星形细胞瘤发生的关系。１材料和方法１．１材料选自我院神经外科手术切除星形细胞瘤标本...     

胃癌组织中P^53基因及其产物变化的研究

近来的研究表明，肿瘤的发生是由于癌基因活化及抑癌基因突变所致。Ｐ５３基因为一抑癌基因，与多种肿瘤的发生有关。为探索Ｐ５３基因在胃癌发生过程中的作用，我们运用多聚酶链反应—单纯构象多态分析（ＰＣＲ—ＳＳＣＰ）及免疫组化技术对胃癌组织中Ｐ５３基因及其产物...     

Co-expression of p53 and MDM2 in human atherosclerosis: implications for the regulation of cellularity of atherosclerotic lesions

Atherosclerosis is a fibroproliferative disease of the arterial intima. It was recently found that wild-type p53 (wt p53) accumulates in human atherosclerotic tissue. Wt p53 is a cell cycle regulator involved in DNA repair, DNA synthesis, cell differentiation, and apoptosis and might therefore make an important contribution to the cellularity of atherosclerotic plaques. The product of the MDM2 gene is a nuclear protein which forms a complex with p53, thereby inhibiting the negative regulatory effects of wt p53 on cell cycle progression. In order to address a potential role of the interaction of p53 with MDM2 for the regulation of cellularity in atherosclerotic tissue, 22 carotid atheromatous plaques from patients undergoing endarterectomy were studied to determine the presence of p53 immunoreactivity (IR), MDM2 IR, cell proliferation as evidenced by MIB1/Ki-67 IR and DNA fragmentation by in situterminal transferase-mediated dUTP 3′ end labelling (TUNEL), as a marker for apoptosis. p53 IR localized to areas with evidence of chronic inflammation (22/22) and was observed in virtually all cell types in 68·79±7·51 per cent of the nuclei. p53 staining in the control tissue from human internal mammary arteries was present in 0·2±0·29 per cent of the cells (P≤0·002). MDM2 IR was present in all cases (22/22) in macrophages and smooth muscle cells (SMCs) in 60·53±8·32 per cent of the nuclei (controls: 0·8±0·65 per cent, P≤0·002) and co-localized with p53 IR as shown by examination of adjacent sections and by double immunofluorescence labelling. Importantly, co-immunoprecipitation and western blot analysis revealed that p53 and MDM2 were physically associated, indicating that MDM2–p53 complex formation takes place in vivoin human atherosclerotic tissue. Positive TUNEL staining and MIB1/Ki-67 IR present in 3·01±1·27 per cent of the nuclei (controls: 0 per cent, P≤0·002) localized to the same plaque compartments as p53 IR and MDM2 IR. Thus, the fate of cells with p53 accumulation may depend on the interaction and the stoichiometry of the p53 and MDM2 proteins. Cells were indeed found with strong p53 accumulation and nuclear morphology typical for apoptosis and there were a few MIB1/Ki-67-positive cells with co-expression of MDM2, indicating a possible role for MDM2 in reversing the negative regulatory effects of p53 for cell cycle progression. The nuclear co-localization of p53 IR with MDM2 IR and the co-immunoprecipitation assay indicate the presence of p53–MDM2 complex formation in vivo in human atherosclerotic tissue. The destiny of individual p53 and MDM2-co-expressing cells either to undergo p53-dependent apoptosis or to re-enter the cycle of cell proliferation may depend on the relative ratios of the two proteins. p53 and MDM2 may therefore play an important role in regulating cellularity and inflammatory activity in human atherosclerotic plaques. © 1998 John Wiley & Sons, Ltd.     

骨肿瘤MDM2和p53基因的改变

目的从基因水平研究ＭＤＭ２和ｐ５３基因在骨肿瘤中的表达，探讨其在骨肿瘤发生发展中的作用。方法用地高辛标记原位杂交技术研究了３８例骨肿瘤（骨肉瘤１２例，软骨肉瘤１０例，骨巨细胞瘤１４例，软骨母细胞瘤２例）ＭＤＭ２和ｐ５３的表达情况，并分析两种基因表达之间的相互关系。结果ＭＤＭ２在骨肉瘤、软骨肉瘤和骨巨细胞瘤中的阳性率分别为４１．７％、５０．０％和３５．７％。ｐ５３的阳性率分别为５８．３％、４０．０％和２１．４％。２例软骨母细胞瘤ＭＤＭ２和ｐ５３均为阳性。ＭＤＭ２与ｐ５３基因表达呈显著正相关（Ｐ＜０．００５）。结论ＭＤＭ２和ｐ５３基因改变是骨肿瘤的一种常见现象，可能参与骨肿瘤的发生与发展。     

No evidence for functional inactivation of wild-type p53 protein by MDM2 overexpression in gastric carcinogenesis

Inactivation of wild-type p53 during gastric carcinogenesis is usually caused by mutations within exons 5–8 of the p53 gene leading to mutated, usually immunohistochemically detectable p53 proteins. However, functional inactivation of wild-type p53, mimicking mutational inactivation, may also result from binding to overexpressed MDM2 protein. While these two mechanisms of p53 inactivation are considered to be mutually exclusive, no data exist as to whether MDM2 overexpression occurs during gastric carcinogenesis. MDM2 protein overexpression was therefore studied in relation to p53 protein accumulation in gastric carcinogenesis. Forty-five paraffin-embedded gastrectomy specimens from early gastric carcinomas were examined for the presence of chronic active gastritis, chronic atrophic gastritis, subtypes of intestinal metaplasia, and dysplasia. The Lauren type was reassessed for all early carcinomas. p53 protein accumulation was examined using the monoclonal antibody DO-7. MDM2 protein overexpression was assessed with the monoclonal antibody SMP-14. Complete absence of nuclear p53 protein accumulation was observed in chronic active gastritis, chronic atrophic gastritis, and intestinal metaplasia, irrespective of the subtype. In gastric dysplasia (one mild, two moderate, one severe), only severe dysplasia was p53-positive. Intestinal-type (n=20) and diffuse-type early gastric carcinoma (n=25) were p53-positive in 70 and 52 per cent of the cases, respectively. MDM2 protein overexpression was not observed during gastric carcinogenesis, either in the p53-positive or in the p53-negative cases. In conclusion, it appears that functional inactivation of wild-type p53 by MDM2 protein overexpression plays no role in (early) gastric carcinogenesis. © 1998 John Wiley & Sons, Ltd.     

Overexpression of p53 protein and MDM2 in papillary carcinomas of the thyroid: Correlations with clinicopathologic features

Expression of p53 protein and MDM2 was evaluated in paraffin-embedded tissue from 78 patients with papillary carcinomas of the thyroid (PCT), in order to elucidate the relationship between them and their correlations with some clinicopathologic features implicated in tumor progression. These proteins were expressed in nuclei of tumor cells, but not in non-tumor cells. Staining was defined as positive when 10% or more of tumor cells expressed these proteins. The number of cases positive for p53 protein was 21/78 (27%), and that positive for MDM2 was 26/78 (33%). Co-overexpression of p53 protein and MDM2 was observed in 12/78 cases (15%). A significant positive relationship was found between them (P < 0.01); p53-positive cases tended to be also positive for MDM2 and vice versa. Statistical analysis revealed that overexpression of p53 protein significantly correlated with large tumor size (P = 0.0271) and the presence of capsular invasion (P = 0.04). There were significant positive correlations between tumor size and intrathyroidal invasion and between tumor size and capsular invasion in PCT, suggesting that p53 protein overexpression is associated only with tumor progression (tumor size). However, we could not find any significant correlations between MDM2 expression and clinicopathologic features. Our findings suggest that overexpression of p53 protein and MDM2 in papillary carcinoma of the thyroid is associated with the progression of the tumors, and that p53 may be a marker of the progression of PCT.     

Immunohistochemical inactivation of p14ARF concomitant with MDM2 overexpression inversely correlates with p53 overexpression in oral squamous cell carcinoma

The CDKN2 gene encodes two structurally different proteins: a cyclin-dependent kinase inhibitor called p16, which regulates retinoblastoma protein (pRb)-dependent G1 arrest, and a cell cycle inhibitor designated p14ARF, which arrests cell growth in G1-S and also in G2-M. Whereas inactivation of p16 has been described as a frequent event in various cancers, including oral cancer, the current function of p14ARF is still poorly understood. A physical association between p14ARF and MDM2 blocks MDM2-induced p53 degradation, resulting in increased levels of p53, which in turn leads to cell cycle arrest. The present study immunohistochemically examined the expression of p16 and p14ARF together with pRb, MDM2 and p53 status in a series of oral cancers. The results showed that p14ARF was frequently absent in the oral cancers (15/37, 41%) as was p16 immunostaining. Concomitant immunopositivity for p14ARF and MDM2 overexpression was frequently observed in a subset of the cancers, whereas an inverse correlation between p14ARF and MDM2 expression and the diffuse staining of p53 was clearly detected. Moreover, the results showed that in most cases of oral cancer (35/37, 95%) at least one protein was altered, and lymph node metastasis was more frequent in the tumors with alterations in both the p16/pRb and p14ARF/p53 pathway (8/16, 50%) than in the tumors with one or no alteration of these two major pathways.     

p53 Mutation and MDM2 amplification in inflammatory myofibroblastic tumours

AIMS: The pathogenic mechanism and predictive indicators of biological behaviour of inflammatory myofibroblastic tumour are poorly understood. We investigated molecular abnormalities of p53 and MDM2 in order to assess whether these play an important role in pathogenesis, and whether they also contribute to clinicopathological aggressive phenotype in inflammatory myofibroblastic tumour. METHODS AND RESULTS: We compared the immunohistochemical expression of calponin, h-caldesmon, ALK, and p53 gene mutation and MDM2 gene amplification with clinicopathological findings in 15 cases of inflammatory myofibroblastic tumour. Histologically, cellular atypia was observed in five (33.3%) out of 15 cases. Local recurrences were observed in two (14.3%) of 14 informative cases, but no distant metastasis was observed. The expression of calponin (9/14; 64%) but not h-caldesmon (0/14; 0%) was seen, which suggested myofibroblastic differentiation. ALK expression was seen in eight (53.3%) out of 15 cases, particularly in patients under 40 years old. Nuclear expression of p53 protein was recognized in only one (6.7%) of 15 cases, and polymerase chain reaction single-strand conformation polymorphism followed by direct sequencing revealed p53 gene missense mutations in two (13.3%) of 15 cases. Nuclear expression of MDM2 was seen in four (26.7%) of 15 cases, and the MDM2 gene amplification was observed in two of the four cases. CONCLUSION: Inflammatory myofibroblastic tumour shows a wide spectrum of cellular atypia and biological behaviour with p53 and MDM2 expression. However, the alterations in the p53 pathway seem not to play a major role in the pathogenesis of inflammatory myofibroblastic tumour.     

p53 expression in CMV-infected cells: association with the alternative expression of the p53 transactivated genes p21/WAF1 and MDM2

The p53 tumour suppressor gene is a cell cycle regulator, able to induce cell cycle arrest to allow DNA repair or apoptosis. The molecular mechanisms underlying p53 action imply transactivation of p53 dependent genes such as WAF1 (for wild type p53 associated fragment 1) and the murine double minute (MDM2) gene. In some cases, inactivation of the p53 gene results from p53 gene mutations leading to p53 protein accumulation, but in others it may results from mechanisms other than mutation, such as interaction with viral or cellular proteins. The expression of p53 protein and p53 transactivated gene proteins p21/WAF1 and MDM2, combined with in situ detection of apoptosis, was studied in specimens of CMV-infected patients as an in vivo model of p53 alteration not due to point mutation. p53 positivity was found in CMV + cells in different tissues, in cells with typical inclusion bodies, and in in situ hybridization and immunohistochemistry CMV + cells without inclusions (hidden infection). Although this p53 reactivity was accompanied by the expression of MDM2 and p21/WAF1 proteins, the patterns of MDM2 and p21/WAF1 protein expression were mutually exclusive, and were associated with the presence or absence of inclusion bodies. Nuclei bearing inclusion bodies were usually MDM2 +, p21/WAF1?, while hidden infected cells were usually MDM2?, p21/WAF1 +. Apoptosis was not detected in any tissue section from CMV-infected patients. Two alternative patterns were found in CMV-infected tissues: p53 +, p21/WAF1 +, MDM2?, or p53 +, p21/WAF1?, MDM2 + protein expression. These may represent examples of p53 dependent alternative effects in the course of CMV infection. Early stages are represented by CMV + cells without inclusion bodies, which display p53 and p21/WAF1 expression, suggesting that p53 could be acting as a growth suppressor protein. Late CMV infection is represented by cells harbouring inclusion bodies. These cells showed a p53 +, p21/WAF1?, MDM2 + profile, consistent with MDM2 mediated p53 inactivation. The absence of p21/WAF1 expression and lack of apoptosis suggest that the p53 protein expressed by MDM2 + cells could be functionally inactivated in CMV-infected cells with inclusion bodies. Previous studies have suggested that p53 inactivation by MDM2 over-expression occurs in sarcomas and lymphomas. Our observations seem to indicate that this mechanism of MDM2 mediated p53 inactivation may play a role in the late phase of CMV infection.     

High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas

The p53 tumor suppressor is mutated in most human tumors. MDM2, a well-known inhibitor of p53, is overexpressed in a large number of tumors, suggesting that increased levels of MDM2 also contribute to tumorigenesis. A novel p53 inhibitor, MDM4, was more recently identified. The role of MDM4 in cancer development is not well understood. We set out to examine the levels of MDM4 by immunohistochemistry in head and neck squamous carcinomas (HNSC) to ask whether high MDM4 levels could contribute to its development and progression. In addition, MDM2 and p53 levels were examined to identify overlapping expression patterns. MDM4 is present at high levels in 50% of HNSC. In addition, overexpression of MDM2 was detected in 80% of tumors, many of which were also positive for MDM4. A subset of tumors displayed high levels of all 3 proteins. Sequencing of the p53 gene revealed that tumors with positive immunoreactivity for MDM2 or MDM4, some of which also had high levels of p53, did not carry mutations in this gene. Thus, the detection of p53 by immunohistochemistry was not synonymous with the presence of p53 mutations. Expression of both MDM2 and MDM4 in tumors without p53 mutations strongly suggests that MDM2 and MDM4 inhibit the activity of this tumor suppressor in HNSC.     

p53 gene mutation and MDM2 overexpression in a case of primary malignant fibrous histiocytoma of the jejunum

Primary malignant fibrous histiocytoma of the gastrointestinal tract is extremely rare. To date, only 10 cases of primary malignant fibrous histiocytoma arising in the small intestine have been reported in the English literature. We describe here the genetic alterations and morphologic features of a primary malignant fibrous histiocytoma arising in the jejunum. Immunohistochemically, the tumor cells expressed vimentin, CD68 and alpha-1-antitrypsin, but were negative for other markers. Ultrastructurally, they showed features of fibroblasts and histiocytes. Immunohistochemical overexpression of p53 and MDM2 was observed. Mutation analysis of the p53 gene detected a missense mutation in codon 158 of exon 5. Our results suggest that p53 gene mutations and MDM2 overexpression may play an important role in the tumorigenesis. To our knowledge, the present report is the first genetic study of this rare lesion.