survivin、p53和bcl-2蛋白在非霍奇金淋巴瘤的表达及其意义

 目的 探讨survivin、p53和bcl-2蛋白在非霍奇金淋巴瘤（NHL）中的表达与肿瘤细胞凋亡和预后的关系。方法 应用TdT介导的dUTP缺口末端标记（TUNEL）技术和免疫组织化学SP法,检测82例NHL和17例良性淋巴结病变中细胞凋亡和survivin、p53和bcl-2蛋白的表达水平。结果 40.2 %（33／82）NHL表达 survivin,在BCL、TCL的表达阳性率分别为46.5 %、33.3 %,而仅在11.8 %（2／17）良性淋巴结病变中弱阳性表达,二者差异有统计学意义（P＜0.05）,但与NHL的免疫表型无关（P＞0.1）。NHL中survivin的表达与突变型p53蛋白积聚（P＜0.05）和肿瘤细胞凋亡的下降相关（P＜0.001）,但与bcl-2蛋白表达无关（P＞0.1）,且阳性表达患者的平均生存时间明显短于无表达患者（P＜0.05）。结论 survivin基因可能通过其凋亡抑制功能在NHL的发生、发展中有一定作用,且其与突变型p53蛋白的积聚显著相关,但与bcl-2蛋白表达无关;并可能是NHL的一个新的预后不良因子。     

抑癌基因p16、Rb在急性淋巴细胞白血病患者中的表达及其临床意义

 目的 观察抑癌基因p16、Rb在急性淋巴细胞白血病（ALL）患者中的蛋白表达水平，探索其在ALL发病中的临床意义。方法 应用Western Blot及SP免疫组织化学染色技术检测抑癌基因p16、Rb在ALL患者白血病细胞中的蛋白表达水平。结果 32.14 % ALL患者p16蛋白表达缺失，与对照组比较差异具有统计学意义（P＜0.05）；免疫组织化学染色白血病细胞阳性率降低为11.3 %，与对照组比较差异具有统计学意义（P＜0.05）；28.57 % ALL患者pRb蛋白表达缺失，与对照组比较差异有统计学意义（P＜0.05）；免疫组织化学染色白血病细胞阳性率降低为41.6 %，与对照组比较差异有统计学意义（P＜0.05）；ALL患者p16与pRb蛋白表达水平经等级相关分析呈负相关（rs =－0.9247，P＜0.001）。结论 p16、Rb基因的异常表达在ALL的发生及演变过程中有重要意义，两者之间可能存在着负反馈调节机制。     

3q27-3q29相关的p63蛋白表达在弥漫性大B细胞淋巴瘤中的意义

 目的　探讨3q27-3q29相关的p63蛋白表达在弥漫性大B细胞淋巴瘤（DLBCL）中的意义。方法　应用免疫组织化学EnVision二步法检测102例DLBCL与15例反应性淋巴组织增生（RHL）中p53蛋白和3q27-3q29相关的p63蛋白的表达并进行随访。结果　p53、p63蛋白在DLBCL中的阳性率分别为62 %和56 %,在RHL中的阳性率分别为0和13 %,p53、p63蛋白在DLBCL与RHL中比较差异均有统计学意义（P＜0.05）;p53、p63蛋白的表达在Ⅰ+Ⅱ期中的阳性率分别为48.3 %和41.4 %,在Ⅲ+Ⅳ期中的阳性率分别为79.5 %和75 %,差异有统计学意义（P＜0.05）;p53、p63蛋白的表达在生发中心B细胞型（GCB型）中的阳性率分别为28 %和28 %,在非GCB型（non-GCB型）中的阳性率分别为72.7 %和64.9 %,差异均有统计学意义（P＜0.05）。p53、p63蛋白表达与患者性别、年龄、有无B症状和发病部位等无相关性（P＞0.05）。p53蛋白表达与p63蛋白表达呈正相关性（r＝0.629,P＜0.05）。p53、p63蛋白表达阴性组的5年总体生存率高于阳性组（38 %∶6 %,51 %∶4 %）,差异有统计学意义（P＜0.05）。结论　p63可能作为癌基因与p53共同参与了DLBCL的发生和发展,两者在肿瘤的发生中可能起着协同作用;联合检测p63蛋白和p53蛋白在DLBCL中的表达,可能成为判断DLBCL预后指标之一。     

EB病毒、p53、bcl-2、c-myc和Rb蛋白在非霍奇金淋巴瘤发病及病情演化中的价值

目的：探讨EB病毒（EBV）与bcl-2、突变型p53、c-myc和Rb蛋白在非霍奇金淋巴瘤（NHL）发病及病情演化中的价值。方法：用免疫组化S-P法对140例NHL进行EBV、bcl-2、突变型p53、c-myc和Rb蛋白检测，并选择同期增生性淋巴结炎51例作为对照组。结果：EBV、p53、bcl-2和c-myc蛋白在NHL表达的阳性率和Rb蛋白表达的阴性率均高于对照组，两组比较差异有显著性（P〈0.05）；EBV与突变型p53、bcl-2、Rb、c-myc蛋白在NHL中表达无相关性（P〉0．05）：突变型p53、bcl-2在不同恶性程度NHL中的表达有显著性差异（P〈0．05）；EBV、突变型p53、bcl-2、Rb、c-myc蛋白在不同临床分期NHL中的表达有显著性差异（P〈0．05）。结论：EBV、突变型p53、bcl-2、和c-myc蛋白与NHL的发病存在正相关关系，Rb蛋白则为负相关关系；EBV和突变型p53、bcl-2、c-myc、Rb蛋白在NHL的发病中系相对独立的因素；突变型p53、bcl-2蛋白表达与NHL恶性程度成正相关关系；EBV、突变型p53、bcl-2、和c-myc蛋白与NHL病情恶化成正相关关系，Rb蛋白则为负相关关系。     

p53 mRNA、MDM2蛋白在肺癌组织中的表达

目的 探讨原发性肺癌组织中MDM2、p53 mRNA表达水平及其与临床预后的关系。方法 采用免疫组织化学Doko Envision^TM二步法、逆转录聚合酶链反应（RT－PCR）方法，分别检测52例肺癌组织中MDM2、p53 mRNA的表达情况。结果在52例肺癌组织中有23例（44．2％）MDM2蛋白表达阳性，其中3例小细胞肺癌全部阳性，在非小细胞肺癌中MDM2蛋白呈过表达，低分化癌明显高于高、中分化肺癌（P＜0．01）。有27例（51．9％）肺癌组织p53 mRNA表达阳性，其中I期肺癌占82．3％（14例），Ⅱ期肺癌占71．4％（10例），明显高于Ⅲ期肺癌的14．3％（3例）。高中分化肺癌的p53 mRNA表达显著高于低分化肺癌（P＜0．05）。结论 MDM2蛋白在低分化肺癌中呈过表达，p53 mRNA在早期和高中分化肺癌中呈高表达，它们分别是肺癌发生发展过程中不同的2个基因事件。     

肺癌MTS1/p16和p53表达与细胞增殖

（目的〕研究肺癌中MTS1／p16和p53基因产物的表达与细胞增殖的关系。〔方法〕应用SP免疫组织化学方法研究62例肺癌组织中p16蛋白和p53蛋白的表达情况，并进行增殖细胞核抗原检测，计算细胞增殖指数（PI）。(结果)62例肺癌组织中p16蛋白和p53蛋白阳性率分别为58．1％和59、7％。晚癌p16蛋白的阳性率明显高于小细胞癌（p＜0.05）；淋巴结转移阳性组p16蛋白的表达显著低于阴性组（P＜0．05）；PI分级为巨级的p16蛋白表达显著高于Ⅳ级（p＜0.05）。不同组织类型肺癌中p53蛋白的表达未见明显差异，淋巴结转移阳性组p53蛋白的表达高于阴性组（p＜0.01〕；不同PI分级中p53蛋白的表达，N级明显高于1级和Ⅱ级（P＜0．05），三级明显高于1级（p＜0．05）和Ⅱ级（P＜0.01）。p16蛋白低表达和p53蛋白过度表达之间未见明显相关性。（结论〕提示p16蛋白低表达和p53蛋白过度表达均有促进肺癌细胞增殖的作用，p16蛋白的表达与肺癌的细胞分化有关，p53蛋白过度表达对肺癌细胞的转移起重要作用。抑癌基因p53对MTS1／p16基因无明显调控作用。检测p53蛋白表达可作为肺癌诊断的一项新指标。     

PTEN和Beclin-1在儿童非霍奇金淋巴瘤组织中的表达及其临床意义

目的:探讨PTEN、Beclin-1在儿童非霍奇金淋巴瘤（non-Hodgkin's lymphoma,NHL）组织中的表达特点及其临床意义。方法:采用免疫组织化学SP法检测儿童NHL及淋巴结反应性增生（reactive hyperplasia,RH）组织中PTEN蛋白、Beclin-1蛋白的表达,应用χ2检验比较此两种蛋白在NHL及RH组织中的阳性表达率,进一步分析此两种蛋白与患儿临床病理因素（性别、年龄、T/B分型、St.Jude分期、LDH水平、有无B症状、Ki-67及IPI危险度分层）的关系及两者的相关性。结果:儿童NHL组织中PTEN蛋白阳性率为47.2%,低于RH组织（80.8%）（χ2=7.161,P＜0.05）。PTEN蛋白的表达与NHL患儿IPI危险度分层及LDH水平相关。儿童NHL组织中Beclin-1蛋白阳性率为50.0%,低于RH组织（84.6%）（χ2=7.902,P＜0.05）。Beclin-1的表达与NHL患儿的临床病理特征无明显相关性。Spearman等级相关分析显示PTEN蛋白和Beclin-1蛋白在儿童NHL组织中的表达呈正相关（r=0.501,P＜0.05）。结论:PTEN基因和Beclin-1基因在儿童NHL中缺失或失表达,可能促进疾病发生发展。此两种抑癌基因在NHL的发生中可能起协同作用,联合检测可能有助于诊断及预后判断。     

p53基因突变对非小细胞肺癌TSG101/MDM2信号通路的影响

目的探讨p53基因突变在肺癌中对TSG101/MDM2信号通路影响的临床病理学意义。方法采用免疫组织化学方法检测185例肺癌组织标本中TSG101、MDM2及p53的表达,用聚合酶链反应单链构象多态性(Polymerase Chain Reaction ,single-strand conformation polymorphism, PCR-SSCP)分析法检测p53突变情况,以及Western blot检测TSG101在肺癌组织和正常肺组织中的表达。结果（1）肺癌组中p53蛋白的总阳性率为80.54%(149/185),PCR-SSCP检测结果显示总突变率为56.67%（17/30）,p53蛋白表达与病理分期、淋巴结转移有相关性（P<0.05）;TSG101蛋白的低表达率为58.92%(109/185),Western blot结果显示TSG101在癌组织中的表达明显低于对照组（P<0.05）,TSG101蛋白表达与病理分期、分化、淋巴结转移有相关性（P<0.05）;MDM2蛋白的过表达率为77.84%(144/185),MDM2蛋白表达与病理分期、淋巴结转移有相关性（P<0.05）。(2)在p53阳性的149例中TSG101阳性76例,MDM2阳性139例,在p53阴性的36例中TSG101阳性33例,MDM2阳性5例。p53与TSG101两者共表达率为41.08%,一致性为42.70%。p53与MDM2两者共表达率为75.14%,一致性为91.89%。结论（1）p53/MDM2上调与TSG101表达下调肺癌的发生及生物学行为有关。(2)当p53突变时, TSG101与MDM2的表达呈负相关关系。     

MDM2和p53在反应性及肿瘤性星形胶质细胞中的表达

目的：检测MDM2和p53蛋白在星形胶质细胞反应性增生与星形胶质细胞瘤中的表达，探讨二者在胶质瘤形成和发展中的作用及其相关性。方法：应用组织芯片和免疫组化染色技术检测正常脑组织、星形胶质细胞反应性增生、低级别（Ⅰ-Ⅱ级）和高级别（Ⅲ-Ⅳ级）星形胶质细胞瘤中MDM2和p53蛋白的表达情况。结果：正常脑组织中MDM2和p53蛋白均呈阴性表达；反应性增生组、低级别肿瘤组及高级别肿瘤组中MDM2蛋白的阳性率分别为32.7％（16／49）、59．2％（29／49）、80．0％（40／50）；p53蛋白的阳性率分别为27．3％（12／49）、57．1％（28／49）、82．0％（41／50）。二者阳性表达率均随着病变恶性程度的增加而升高，MDM2和p53在各实验组间的比较差异均有统计学意义（P〈0．05）；且MDM2和p53表达密切相关（P〈0．05）。结论：MDM2和p53在星形胶质细胞反应性增生及星形胶质细胞瘤中均呈不同程度的过度表达，且随着病变恶性程度的增加表达水平增高，MDM2扩增和p53突变是胶质瘤发生的早期事件，二者的联合检测可能会对星形胶质细胞反应性增生与低级别胶质细胞瘤的鉴别诊断以及星形胶质细胞瘤的早期诊断提供一定的依据。     

鼻咽癌p53 p21 WAF1和MDM2蛋白异常表达的临床意义

目的：探讨p53、p21^WAF1、MDM2蛋白在原发鼻咽癌（NPC）异常表达的临床意义。方法：采用LSAB法检测69例原发NPC组织中p53、p21^WAF1和MDM2蛋白的表达状况。结果：1）p53、p21^WAF1和MDM2蛋白在原发NPC组织的阳性表达率分别为79．7％、84．1％、和82．6％；高表达率分别为50．7％、46．4％和31．9％。2）p53蛋白的高表达率随TNM分期的升高而增多，P＝0．042。3）p53或MDM2蛋白高表达者的复发间期显著短于相应蛋白低表达／阴性者，分别P＝0．038和P＝0．002。4）p53和MDM2蛋白同时高表达者、MDM2蛋白高表达同时p21^WAF1蛋白低表达／阴性者的复发间期明显短于对照组，分别P＜0．001；p21^WAF1蛋白高表达同时p53蛋白低表达／阴性者、p53和MDM2蛋白同时低表达／阴性者的复发间期显著长于对照组，分别P＝0．002和P＝0．014。5）p53和MDM2蛋白高表达同时p21^WAF1蛋白低表达／阴性者的复发间期明显短于对照组，P＜0．001；p53和MDM2蛋白低表达阴性同时p21^WAF1蛋白高表达者的复发间期明显长于对照组，P＝0．002。结论：p53或MDM2蛋白高表达提示有促进NPC复发的作用，p21^WAF1蛋白高表达提示有抑制NPC复发的作用。单独检测p53或MDM2蛋白在原发NPC组织的表达情况可以和为预测NPC复发倾向和临床预后的参考指标；如同时检测p53、MDM2和p21^WAF1蛋白的两项或三项指标，预测意义更理想。     

Overexpression of MDM2 and p53 protein is infrequently but significantly associated with progression of human prostatic adenocarcinoma

In the present immunohistochemical study using anti-p53 (DO-7) and anti-MDM2 (IF2) antibodies, we determined the frequency of p53 and MDM2 protein expression in a series of 115 primary prostatic adenocarcinomas (stage A1 to D2) and evaluated the reliability of p53 and MDM2 immunoreactivity as an indicator for tumor progression. Overall, 13.9% (16/115) of surgically resected tumors were positive for anti-p53 antibody. A significantly higher association of immunoreactivity for p53 was detected in both high-grade (4/16, 25%; p<0.05) and advanced stage tumors (14/73, 19.1%; p<0.05) compared with that of other grade or stage. Positive staining for anti-MDM2 antibody was observed in only 4.3% (5/115) of the tumors examined. However, nuclear MDM2 protein overexpression, detected as focal and markedly heterogeneous staining, was sometimes observed especially in advanced stage tumors (4 stage C and 1 stage D tumors), and was significantly more common in locally advanced cancers (p<0.05) than in those of other stage. Only 2 cases (1.7%) exhibited positive staining with both p53 and MDM2 antibodies. These findings suggest that p53 and MDM2 alterations might play significant roles in the development and progression of some advanced stage or high-grade prostatic cancers, although MDM2 and p53 protein overexpression is infrequent in prostatic adenocarcinoma.     

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。     

MDM2 overexpression with alteration of the p53 protein and gene status in oral carcinogenesis.

In this study, to better understand the mechanism of oral squamous cell carcinoma (SCC) carcinogenesis, alterations of the p53 gene and overexpression of MDM2 and p53 were analyzed in 38 oral SCC samples. Twelve of the 38 specimens revealed mutant-type p53. Moreover, coexpression of MDM2 and p53 was found most frequently in dysplastic lesions (P < 0.05). Expression of MDM2 and p53 was significantly increased in accordance with the histological progression of multistep carcinogenesis (P < 0.05). No significant correlation was found between the expression of MDM2 and the alteration of p53 protein or p53 gene status. MDM2 overexpression with mutant p53 was significantly associated with poorly differentiated SCCs (P < 0.05) and tumor stages III and IV of oral SCCs (P < 0.05). These results suggest that MDM2 overexpression is an early event in oral carcinogenesis through the functional inactivation of the wild-type p53, and corresponding alterations of MDM2 and p53 contribute to the oral carcinogenesis. We propose that it would be clinically more instructive to evaluate MDM2 overexpression combined with p53 gene status, compared to the evaluation of either MDM2 or p53 alteration alone.     

MDM2 gene amplification and expression in non-small-cell lung cancer: immunohistochemical expression of its protein is a favourable prognostic marker in patients without p53 protein accumulation.

MDM2 is an oncoprotein that inhibits p53 tumour-suppressor protein. Amplification of the MDM2 gene and overexpression of its protein have been observed in some human malignancies, and these abnormalities have a role in tumorigenesis through inactivation of p53 function. To determine the clinicopathological and prognostic value of MDM2 abnormalities in non-small-cell lung cancer (NSCLC), MDM2 gene amplification and its protein expression status were analysed in surgically resected materials. MDM2 gene amplification was detected in only 2 (7%) of the 30 tested patients. MDM2 protein was found immunohistochemically in a total of 48 (24%) of the 201 patients. MDM2 protein was slightly frequently observed in patients with adenocarcinoma, but its presence or absence was not associated with clinicopathological factors such as T-factor, N-factor, stage, tumour size, differentiation or p53 protein status. Overall, MDM2-positive patients tended to have a better prognosis (P = 0.062). In particular, among immunohistochemically p53-negative patients (n = 110), those with positive MDM2 protein expression showed significantly better prognosis (P = 0.039) and, in a multivariate analysis, MDM2 protein status was a favourable prognostic factor (P = 0.037). In contrast, among p53-positive patients (n = 91), there was no difference in prognosis depending on MDM2 protein status. Thus, in the NSCLC patients studied, MDM2 gene amplification was a minor event, but expression of its protein, which was often observed immunohistochemically, was a favourable prognostic marker, especially among patients without p53 protein accumulation. Further study is needed to determine how MDM2 protein expression results in a better prognosis.     

MDM2 Overexpression with Alteration of the p53 Protein and Gene Status in Oral Carcinogenesis

In this study, to better understand the mechanism of oral squamous cell carcinoma (SCC) carcinogenesis, alterations of the p53 gene and overexpression of MDM2 and p53 were analyzed in 38 oral SCC samples. Twelve of the 38 specimens revealed mutant-type p53. Moreover, coexpression of MDM2 and p53 was found most frequently in dysplastic lesions ( P < 0.05). Expression of MDM2 and p53 was significantly increased in accordance with the histological progression of multistep carcinogenesis ( P < 0.05). No significant correlation was found between the expression of MDM2 and the alteration of p53 protein or p53 gene status. MDM2 overexpression with mutant p53 was significantly associated with poorly differentiated SCCs ( P < 0.05) and tumor stages III and IV of oral SCCs ( P < 0.05). These results suggest that MDM2 overexpression is an early event in oral carcinogenesis through the functional inactivation of the wild-type p53 , and corresponding alterations of MDM2 and p53 contribute to the oral carcinogenesis. We propose that it would be clinically more instructive to evaluate MDM2 overexpression combined with p53 gene status, compared to the evaluation of either MDM2 or p53 alteration alone.     

Heterogeneous distribution of P53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with P53 gene mutation

Although the tumor suppressor p53 protein (P53) immunoreactivity and its gene (p53) mutation were reported to be significant prognostic indicators for human lung adenocarcinomas, little is known regarding the relationship between the heterogeneous distribution of P53 and its genetic status in each tumor focus and the clinicopathological significance. To determine how P53 is heterogeneously stabilized in patients, we compared P53 expression to both the p53 allelic mutation in exon 2 approximately 9 by polymerase chain reaction-single strand conformation polymorphism using microdissected DNA fractions, and the immunohistochemical MDM2 expression. Of the 48 positive to P53 in 118 lung adenocarcinomas examined, 10 with heterogeneous P53 expression were closely examined. The higher P53 expression foci in 7 of 10 cases were less differentiated, histologically in respective cases, and were frequently associated with fibrous stroma. Two had genetic mutations in exon 7 of the p53 gene in both the high and low P53 expression foci of cancer tissue indicating no apparent correlation between heterogeneous P53 expression and the occurrence of gene mutation. Immunohistochemical expression of MDM2 was significantly lower in high P53 expression areas (p < 0.05, the mean labeling indices of high and low P53 expression areas being 4.2 +/- 5.4% and 13.6 +/- 12.2%, respectively). In addition, among all the 118 cases examined, MDM2 expression was significantly suppressed in cases of p53 gene mutation, simultaneously with P53 overexpression, as compared with cases without both the p53 mutation and expression (p < 0.001). These findings suggest that the heterogeneous stabilization of P53 in human lung adenocarcinomas could be partly due to suppressed MDM2 expression. The overexpression of non-mutated P53 may afford a protective mechanism in human lung adenocarcinomas.     

Wild-type p53 overexpression and its correlation with MDM2 and p14ARF alterations: an alternative pathway to non-small-cell lung cancer.

PURPOSE: We found a relatively reduced frequency of p53 mutation with a much greater frequency of p53 protein overexpression, which reflected stabilization of p53 protein in the absence of p53 gene mutation. Therefore, we investigated the possibility of alternative mechanisms leading to p53 protein stabilization. PATIENTS AND METHODS: We performed gene and protein alteration studies on p53 and its upstream effectors, MDM2 and p14ARF, in tumors from 94 non-small-cell lung cancer (NSCLC) patients. RESULTS: Immunohistochemical and sequencing analyses indicated that 37 tumors showed overexpression of wild-type p53. An absence of nuclear staining of MDM2 protein was found in 95% of these tumors (35 of 37; P < .001). The tumors with negative MDM2 staining showed a significantly high concordance of loss of Akt activity and low MDM2 mRNA expression (P < .001). Sequencing analysis revealed five distinct MDM2 splicing variants disrupting the conserved p53 binding domain. Corresponding variant proteins were detected in three lung cancer cell lines using the Western blot analysis. Our results also indicated that among the tumors with overexpression of the wild-type p53, 92% (34 of 37) showed immunoreactivity to p14ARF (P = .001). In addition, the deregulation of p53 and MDM2 genes was significantly associated with squamous lung cancer (P < .05) and was correlated with advanced stages (P < .05) and poor prognosis (P < .05). CONCLUSION: Our data suggest that immunopositivity of p14ARF together with a low expression of MDM2 contributes to accumulation of the wild-type p53, and that deregulation of the p53-MDM2-p14ARF pathway is important in the pathogenesis and outcome of a subset of NSCLC.     

MDM2/MDMX双靶点抑制蛋白在p53突变型乳腺癌中的作用及机制

目的:明确MDM2/MDMX双靶点抑制蛋白在p53突变型乳腺癌中的抗肿瘤作用及可能机制。方法:采用MTT比色法检测细胞增殖、流式细胞仪测定细胞周期和Annexin V/FITC-PI双染法检测细胞凋亡,明确MDM2/MDMX抑制蛋白对mt-p53乳腺癌的抗肿瘤活性。应用Western Blot检测MDM2、MDMX、p53、p21、PUMA和bax蛋白在mt-p53乳腺癌细胞中的表达水平,初步探讨抑制蛋白抗mt-p53乳腺癌的可能机制。结果:MDM2/MDMX抑制蛋白抑制mt-p53乳腺癌细胞24 h、48 h细胞增殖显著优于Nutlin-3α（P均＜0.05）。MDM2/MDMX抑制蛋白干预mt-p53乳腺癌细胞株24 h和48 h后G0/G1期的细胞比例明显高于Nutlin-3α（P<0.05）。抑制蛋白诱导mt-p53乳腺癌细胞24 h和48 h凋亡比例为（15.97±1.48）%和(17.80±2.21)%(MDA-MB-231细胞);(11.09±2.45)%和(10.44±2.90)%(BT-474细胞)。mt-p53乳腺癌细胞中,抑制蛋白干预组MDM2和MDMX蛋白表达明显降低,p53蛋白则未见明显变化;PUMA、p21和bax蛋白表达则显著增加。结论:MDM2/MDMX抑制蛋白可抑制mt-p53乳腺癌细胞增殖,阻滞周期于G0/G1期和诱导细胞凋亡。抑制蛋白可抑制MDM2和MDMX蛋白的表达,但未能激活p53蛋白表达,以p53非依赖途径上调p21,bax和PUMA蛋白表达发挥抗乳腺癌活性。