Prognostic values of apoptosis-stimulating P53-binding protein 1 and 2 and their relationships with clinical characteristics of esophageal squamous cell carcinoma patients:a retrospective study

Background: Esophageal squamous cell carcinoma(ESCC) is a leading cause of cancer?related death, and new prognostic biomarkers are urgently needed. Apoptosis?stimulating P53?binding protein 1(ASPP1) and 2(ASPP2) have been reported to play important roles in the development, progression, metastasis, and prognosis of cancers, but their roles in ESCC have not been elucidated. In this study, we examined the expression of ASPP1 and ASPP2 in ESCC to evaluate their prognostic values.Methods: The protein expression of ASPP1, ASPP2, and P53 in 175 specimens of ESCC was detected using immuno?histochemical staining; their expression in cancerous and noncancerous tissues was scored according to the stain?ing intensity and the percentage of stained cells. The associations of ASPP1, ASPP2, and P53 with clinicopathologic parameters, overall survival(OS), and disease?free survival(DFS) were analyzed.Results: The protein expression levels of ASPP2 and P53 were significantly higher in cancerous tissues than in paired noncancerous tissues(P < 0.001), whereas the expression levels of ASPP1 in the two groups were similar. In ESCCs, ASPP1 expression was significantly associated with histological differentiation(P = 0.002) and invasive depth(P = 0.014); ASPP2 expression was associated with age(P = 0.029) and histological differentiation(P < 0.001); and P53 expression was associated with age(P and P53 expression. Survival an= 0.021) and tumor size(P alysis revealed that high AS= 0.040). No correlations were found between ASPP1, ASPP2,PP2 expression was significantly associated with increased 5?year OS(P = 0.001) and DFS rates(P ate of ESCC patients(= 0.010) and that high P53 expression was significantly associated with a reduced 5?year DFS rP atio(HR): 0.541, 9= 0.015). Multivariate Cox analysis indicated that ASPP2 was an inde?pendent predictor of OS [hazard r5% confidence interval(CI) 0.363–0.804] and DFS(HR: 0.599, 95% CI 0.404–0.888) of ESCC patients and that P53 was an independent predictor of DFS(HR: 2.161, 95% CI 1.100–4.245).Conclusions: ASPP1 might be involved in the progression of ESCC, and ASPP2 was a potential prognostic biomarker of ESCC and should be evaluated in future studies.

Correlation and Expression of COX-2 and P53 Protein in Basal Cell Carcinoma of Eyelid

The correlation between the expression of COX-2 and p53 protein in basal cell carcinoma （BCC） of eyelid and apoptosis was investigated. Specimens of BCC were collected from 40 cases （aged 28-68 y） at the Department of Pathology, Renmin Hospital of Wuhan University, and Department of Pathology, Zhongnan Hospital of Wuhan University during from 1999 to 2006. Five specimens of paracancerous tissues served as control group. Immunohistochemical staining was performed to detect the expression of COX-2 and p53 in the tissues. The average absorbance （A） and the average positive area rate of COX-2 and p53 protein were measured by image analysis. The positive area rate of COX-2 and p53 protein was analyzed by linear correlation analysis. It was found that COX-2 and p53 proteins were highly expressed in BCC of eyelid, and weakly expressed in paracancerous tissues. Image analysis revealed that the expression of COX-2 and p53 proteins in BCC of eyelid was sig- nificantly higher than that in paracancerous tissues （P〈0.01）. Spearman rank correlation analysis demonstrated a positive correlation between the expression of COX-2 and p53 （r=0.113, P=0.421）. It was concluded that COX-2 can increase the expression of p53 protein, therefore suppressing apoptosis.

EXPRESSIONS OF P_(53), PROLIFERATING CELL NUCLEAR ANITIGEN,BCL-2 PROTEIN AND THEIR SIGNIFICANCE IN SALIVARY ADENOID CYSTIC CARCINOMA

Objective To study the effects of P53, PCNA, Bc1-2 protein and their relationship in salivary adenoid cystic carclnoma(SACC). Methods These protelns were examlned by lmmunohistochemistry. Results overexpressions of Ps, and PCNA were revealed in ACC samples, they were higher than those in (polymorphous adenomas) PA, but expression of Bc1-2 protein was not different between ACC and PA. In 3 subtypes of ACC, expressions of 3 proteins were different. Conciusion Mutations of P53, Bc1-2 may be involed in the occurrence of SACC, expression of PCNA and mutation of P53 may coexist in the development of the SACC.

抗癌方对HepG_2人肝癌细胞株P_(53)蛋白表达的影响

目的观察抗癌方对ＨｅｐＧ２人肝癌细胞株Ｐ５３蛋白表达的影响，以探讨其抗癌作用机理。方法采用ＭＴＴ法分析抗癌方对人肝癌细胞株ＨｅｐＧ２细胞生长的影响。结果抗癌方能明显抑制ＨｅｐＧ２的生长，对ＨｅｐＧ２细胞的半数生长的抑制剂量（ＩＣ５０）为１ｍｇ／ｍｌ。ＬＳＡＢ方法观察发现抗癌方能诱导ＨｅｐＧ２细胞株从相当弱到非常强的比较致密的细胞核染色，且低浓度（０．１ｍｇ／ｍｌ）Ｐ５３蛋白表达诱导作用强于高浓度（１ｍｇ／ｍｌ），几乎将近５０％的细胞出现Ｐ５３蛋白高表达。提示：抗癌方诱导ＨｅｐＧ２Ｐ５３蛋白高达表，可能为其杀伤ＨｅｐＧ２细胞株、诱导其凋亡的机制之一。

髓母细胞瘤中P_(53)、bcl-2及Ki-67的表达及其意义

用免疫组化S P法检测 2 5例髓母细胞瘤中Ki 6 7、P53 及bcl 2基因的表达。结果表明 ,在 2 5例髓母细胞瘤中 ,bcl 2和P53 蛋白的阳性表达率分别为 72 % (18/ 2 5 )和 16 % (4/ 2 5 )。Ki 6 7阳性率平均为 (33.34± 4 .98) % ,其表达与组织学分型有关。说明在髓母细胞瘤中bcl 2蛋白与P53

P_(53)和bcl-2在宫颈上皮内瘤样变及宫颈癌中的表达

目的 探讨P53 和bcl 2表达产物在宫颈癌中过度表达的意义及二者间的相互关系。方法 采用免疫组化SP法分别对 10例宫颈上皮内瘤样变和 5 7例宫颈癌中P53 蛋白和bcl 2蛋白进行了检测 ,并以 11例正常宫颈鳞状上皮作对照。结果 P53 蛋白在CIN中的表达与对照组间差异显著 (P <0 .0 1) ;P53 蛋白在宫颈浸润癌中的表达与对照组间有显著性差异 (P <0 .0 1) ;P53 蛋白在CIN与宫颈浸润癌中的表达差别无显著性 (P >0 .0 5 ) ;P53 蛋白在宫颈浸润癌病理Ⅱ级和Ⅲ级中的表达明显高于病理I级 (P <0 .0 5 ) ;P53 蛋白在宫颈癌结节型中的表达明显高于溃疡型 (P <0 .0 5 ) ;bcl 2蛋白在CIN中的表达强度明显高于对照组 (P <0 .0 5 ) ;bcl 2蛋白在宫颈浸润癌中的表达不仅表达率而且表达强度均明显高于正常对照 (P <0 .0 1) ;bcl 2蛋白在宫颈癌中的表达与在CIN中的表达差别无显著性 (P >0 .0 5 ) ;在宫颈癌中P5 3蛋白表达和bcl 2蛋白的过表达间有明显正相关 (P <0 .0 5 )。结论 P53 和bcl

胃粘膜异型增生的PCNA、P^(53)和C-erbB-2表达及其诊断价值

应用免疫组化SP方法，对65例异型增生胃粘膜PCNA（PC10）、CerbB－2（PAb1）和P53蛋白进行了测定。胃粘膜异型增生Ⅰ级PCNA平均指数22．34％，Ⅱ级32．58％，Ⅲ级46．08％，各组间比较差异有显著性（P＜0．01），PCNA平均指数与异型增生病理分级间有很好地相关性（r＝0．966，P＜0．0005）；Ⅰ、Ⅱ级异型增生无P(53)和C－erbB－2蛋白表达，Ⅲ级中P(53)蛋白阳性8例（32％），C－erbB－2蛋白阳性7例（28％）。本文还就PCNA指数和P(53)、C－erbB－2蛋白表达的意义进行了讨论。

P^(53)、bcl-2蛋白和P-gp的过表达与乳腺癌转移的相关性

目的 :研究 P53、bcl- 2蛋白和 P-耐药糖蛋白 (P- gp)表达与乳腺癌局部淋巴结转移的关系。方法 :应用免疫组化 SABC法检测 6 0例乳腺癌组织中 P53、bcl- 2蛋白与 P- gp表达。结果 :乳腺癌组织中 P53阳性率 5 6 .7% (34/ 6 0 ) ;bcl- 2阳性率 6 3.3% (38/6 0 ) ;P- gp阳性率 38.3% (2 3/ 6 0 ) ;P53、P- gp异常表达均与淋巴结转移有关 (P <0 .0 5 ) ;3种蛋白表达均与组织病理类型无关(P >0 .0 5 )。P53过表达与 P- gp过表达呈正相关 (P <0 .0 1)。结论 :p5 3基因突变及多药耐药基因 (mdr- 1)编码产物 P- gp表达增高对乳腺癌转移有一定影响 ,早期进行乳腺癌 P53和 m dr-

THE QUANTITATIVE MEASUREMENT OF BCL-2, P53 PROTEIN AND PCNA EXPRESSION IN BREAST CARCINOMA AND THEIR CORRELATION WITH PROGNOSIS

To study quantitative index of bci-2, P53, Nroliferating cell nuclear antigen (PCNA),ER and PR in breast carcinoma and their correiation and their relatiousbip with prognosis, the ex expression of bcl-2, P53 and PCNA were studied by immunohistochemical technique. The measurementof ER and PR used enzyme linked affinuity histochemical methods. The quantitative index was analyzed by image technique. All analyses were hased on 60 breast carcinomas. The results were as follows:the more bcl-2 protein, the lower histological graded the longer survival term and the highersurvival rate (P< 0. 05). The quautitative measurement of bcl-2, P53 and PCNA expression were ofvalue in evaluating the degree of differentiation and prognosis in breast carcinoma. The quantitativeand qualitative measurement or p53 protein expression showed a Ⅰwerful evidence in evaluatingprognosis of bcl-2 were more significant in evaluating poor prognosis of breast carcinoma. A relationship between bcl-2 and ER, PR showed a better value for response to endocrine therapy in breastcarcinoma patients.

乳腺癌组织中c-erbB-2、p^(53)和nm23蛋白表达及相互关系和意义

目的 探讨c erbB 2、p53和nm2 3蛋白在乳腺癌组织中的表达与乳腺癌临床病理参数、雌激素受体 (ER)、孕激素受体 (PR)的关系。方法 应用免疫组化ABC法对 5 5例乳腺癌组织中的c erbB 2、p53和nm2 3蛋白表达进行检测。结果 5 5例乳腺癌中c erbB 2、p53及nm2 3的阳性率分别为 49 1 % (2 7/5 5 )、47 3 % (2 6 /5 5 )和 49 1 % (2 7/5 5 ) ,c erbB 2和p53蛋白在乳腺癌中的阳性率与肿瘤病理分级及淋巴结转移有显著意义 (P <0 0 5 ) ,与雌孕激素受体状况呈负相关 (P <0 0 1 )。nm2 3蛋白在乳腺癌中的阳性率与肿瘤病理分级、淋巴结转移有密切的关系 (p <0 0 5 ) ,与雌孕激素受体状呈正相关 (p <0 0 1 )。 70 9% (3 9/5 5 )肿瘤有上述蛋白的异常表达 ,其中 49 1 % (2 7/5 5 )的肿瘤同时有多个蛋白异常表达。结论 肿瘤的多因素分析比单因素分析更有价值 ,癌基因c erbB 2、nm2

人胃癌裸鼠原位移植瘤P_(53)C-erbB-2癌基因蛋白免疫组化和超微结构的研究

目的 为探讨胃癌的分子发病机制和实验治疗提供理想动物模型。方法 采用显微外科原位移植技术 ,将 47例人胃癌标本移植裸鼠胃黏膜层 ,观察原位移植成瘤、侵袭和转移 ,对P53 、C erbB 2、raSP2 1癌基因的表达及形态学特征。结果 从 47例胃癌标本中筛选出人胃腺癌、鳞癌、鳞腺癌三株裸鼠原位移植模型 ,对三种癌蛋白呈阳性表达 ,并与肿瘤生长方式、侵袭深度和淋巴结转移有关 ,超微结构观察移植瘤与来源人胃癌细胞相似。结论 此模型可用于胃癌的分子发病机理、侵袭。

P53凋亡刺激蛋白2分子调控机制的研究进展

P53凋亡刺激蛋白家族(apoptosis stimulating pr-oteins of p53 family, ASPP)是英国科学家Sullivan和卢欣的团队在2001年发现的一类可以调控肿瘤细胞凋亡的家族,其成员包括P53凋亡刺激蛋白1(apop-tosis stimulating protein 1 of p53, ASPP1)、ASPP2和ASPP2家族抑制蛋白([inhibitory member of the ASPPfamily, iASPP)［1-2]。

THE OVEREXPRESSION OF APOPTOSIS-RELATED GENES OF P_53 AND BCL-2 IN CERVICAL CARCINOMA

Objective To investigate the significance of overexpression of p5s and bcl-2 protein in carcinogene- sis of cervix. Methods 10 cases of cervical intraepithelial neoplasis(CIN) and 57 cases of invasive cancer were in- vestigated with immunohistochemistry technique. Results The overexpresion or P53 protein ir CIN and cervical can- cer was significantly higher than that or control, respectively (P<0.01). But there was no significant difference be- tween CIN and cervical cancer(P>0.05). The immunoreactivity of bcl-2 in CIN was much more higher than that of control (P<0.05). The positive rate and immunoreactivity of bcl-2 in cervical carcinoma were both remarkably high- er than those of control (P<0.0l),but there was no significant difference between CIN and cervical carcinoma (P> 0.05). It was also found that there was a remarkably positive correlation between the overexpression of bcl-2 and P53 (P<0.01). Conclusion Because of the loss of wtP53 function,the expression of bcl-2 can not be down-reguated, which is associated with the pathogenesis and development of cervical carcinoma.

Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus

diabetes mellitus(DM)is a disease syndrome characterized by chronic hyperglycaemia.A long-term high-glucose environment leads to reactive oxygen species(ROS)production and nuclear DNA damage.human umbilical cord mesenchymal stem cell(HUcMSC)infusion induces significant antidiabetic effects in type 2 diabetes mellitus(T2DM)rats.Insulin-like growth factor 1(IGF1)receptor(IGF1R)is important in promoting glucose metabolism in diabetes;however,the mechanism by which HUcMSC can treat diabetes through IGF1R and DNA damage repair remains unclear.In this study,a DM rat model was induced with high-fat diet feeding and streptozotocin(STZ)administration and rats were infused four times with HUcMSC.Blood glucose,interleukin-6(IL-6),IL-10,glomerular basement membrane,and renal function were examined.Proteins that interacted with IGF1R were determined through coimmunoprecipitation assays.The expression of IGF1R,phosphorylated checkpoint kinase 2(p-CHK2),and phosphorylated protein 53(p-p53)was examined using immunohistochemistry(IHC)and western blot analysis.Enzyme-linked immunosorbent assay(ELISA)was used to determine the serum levels of 8-hydroxydeoxyguanosine(8-OHdG).Flow cytometry experiments were used to detect the surface markers of HUcMSC.The identification of the morphology and phenotype of HUcMSC was performed by way of oil red“O”staining and Alizarin red staining.DM rats exhibited abnormal blood glucose and IL-6/10 levels and renal function changes in the glomerular basement membrane,increased the expression of IGF1 and IGF1R.IGF1R interacted with CHK2,and the expression of p-CHK2 was significantly decreased in IGF1R-knockdown cells.When cisplatin was used to induce DNA damage,the expression of p-CHK2 was higher than that in the IGF1R-knockdown group without cisplatin treatment.HUcMSC infusion ameliorated abnormalities and preserved kidney structure and function in DM rats.The expression of IGF1,IGF1R,p-CHK2,and p-p53,and the level of 8-OHdG in the DM group increased significantly compared with those in the control group,and decreased after HUcMSC treatment.Our results suggested that IGF1R could interact with CHK2 and mediate DNA damage.HUcMSC infusion protected against kidney injury in DM rats.The underlying mechanisms may include HUcMSC-mediated enhancement of diabetes treatment via the IGF1R-CHK2-p53 signalling pathway.

Upregulation of ASPP2 expression alleviates the development of proliferative vitreoretinopathy in a rat model

AIM:To investigate whether upregulation of apoptosisstimulating p53 protein 2(ASPP2)expression could alleviate the development of proliferative vitreoretinopathy(PVR)in a rat model.METHODS:ASPP2-lentivirus or scrambled-lentivirus were transfected into ARPE-19 cells,followed with measurements of cell cytotoxicity by cell counting kit-8 assay.ASPP2 upregulation was confirmed by Western blotting and immunocytochemistry.Then ARPE-19 cells pretreated with ASPP2-lentivirus were intravitreally injected to Brown Norway rats to induce PVR models.PVR development and retinal function were evaluated by retinal photography and electroretinography,respectively.Finally,epithelial-mesenchymal transition as well as autophagy were investigated in rats’retinas via Western blotting.RESULTS:Protein expression of ASPP2 was significantly upregulated by ASPP2-lentivirus transfection in ARPE-19 cells.The development and progression of PVR were impeded significantly in rats with intravitreal injection of ARPE-19 cells pretreated with ASPP2-lentivirus.Accordingly,retinal functions were less affected and PVR grades were much lower in rats with ASPP2-lentivirus compared to scrambledlentivirus treatment.Moreover,epithelial-mesenchymal transition and autophagy markers were decreased in the retinas of rats treated with ASPP2-lentivirus.CONCLUSION:ASPP2-lentivirus transfected to ARPE-19 cells mitigates the progression of PVR in rat models,which might be partly through reduced autophagy and attenuated epithelial-mesenchymal transition.ASPP2 might stand as a new approach for PVR treatment in the future.

Synergistic impacts of rifampicin and doxorubicin against thioacetamide-induced hepatocellular carcinoma in rats

Background and aims:Combination therapy is a promising new strategy that has been proposed to increase the efficacy of cancer treatment.We aimed to investigate the anti-cancer activity of rifampicin monotherapy and its combination with doxorubicin against hepatocellular carcinoma(HCC).Materials and methods:The in vitro half maximal inhibitory concentration(IC50)and selectivity index(SI)of the drugs under investigation against HepG2 and human lung fibroblast(WI38)cell lines were determined.For the in vivo experiment,male Sprague-Dawley albino rats were injected with thioacetamide at 200 mg/kg twice a week for 90 days;HCC development was confirmed histopathologically.Following HCC induction,the rats were treated with intraperitoneal doxorubicin,rifampicin,or their combination for 45 or 90 days.After sacrifice,the livers were examined histopathologically.The levels of aminotransferases,albumin,bilirubin,malondialdehyde,superoxide dismutase(SOD),catalase(CAT),total antioxidant capacity(TAC),and nitric oxide were measured by spectrophotometry.Alphafetoprotein,cancer antigen 19-9,tumor necrosis factor-alpha,interleukin-6,Bcl-2-associated X protein,caspase 3,caspase 8,and p53 were estimated using ELISA.Results:In vitro,the combination of doxorubicin and rifampicin showed the highest SI of 3.43.In vivo,among the measured markers,the levels of TAC,CAT,SOD,and p53 decreased(P<0.001)and the rest of the measured marker levels increased(P<0.001)in the HCC-bearing rats;after treatment in all groups,all these changes improved toward normal in a time-dependent manner.The combination of doxorubicin and rifampicin optimized the effects of the two individual drugs and exerted the best antioxidant effects.Conclusions:In general,compared with rifampicin or doxorubicin alone,combination therapy has favorable outcomes.Based on our results,the combination of rifampicin and doxorubicin might be applicable for HCC chemotherapy.

Expression and significance of P53 protein and MDM-2 protein in human gliomas

Background P53 is one of the most studied tumor suppressors in the cancer research, and over 50% of human tumors carry P53 mutations. MDM-2 is amplified and/or overexpressed in a variety of human tumors of diverse tissue origin. The aim of this study was to examine the expression of P53 protein and MDM-2 protein in gtiomas, and to investigate the relationship between the expression of the two proteins and the histopathological grades of glioma. The relationship between MDM-2 protein expression and P53 protein expression was also analyzed. Methods The expression of P53 protein and MDM-2 protein was immunohistochemically detected using monoclonal antibodies in 242 paraffin embedded tissues, including 30 normal brain tissues from patients with craniocerebral injury and 212 tissues from patients with primary glioma （grade Ⅰ-Ⅱ group： 5 cases of grade Ⅰ, 119 cases of grade Ⅱ; and grade Ⅲ-Ⅳ group： 53 cases of grade Ⅲ, and 35 cases of grade Ⅳ）. Results The P53 positive rate was significantly higher in the glioma groups than in the control group （P 〈0.0001）. The P53 positive rate was significantly higher in glioma tissues of grade Ⅲ-Ⅳ than in glioma tissues of grade Ⅰ-Ⅱ group （P=-0.001）. The MDM-2 positive rate was significantly higher in glioma groups than in the control group （P 〈0.0001）. There was no significant difference in the MDM-2 positive rate between the two glioma groups （P=0.936）. The expression of P53 protein was not related to expression of MDM-2 protein （P=-0.069） Conclusions Overexpression of P53 protein might be related to the occurrence and progression of glioma. Overexpression of MDM-2 protein may play an important role in glioma tumorigenesis, but may not be involved in glioma progression. The overexpression of MDM-2 protein was an early event in malignant transformation of glioma. MDM-2 may be a key player in glioma in its own right.

PDRG1 at the interface between intermediary metabolism and oncogenesis

PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the p53 and DNA damageregulated gene 1(PDRG1) gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expression has been detected in several tumor cells and in response to genotoxic stress. High-throughput studies identified the PDRG1 protein in a variety of macromolecular complexes involved in processes that are altered in cancer cells. For example, this oncogene has been found as part of the RNA polymerase Ⅱ complex, the splicing machinery and nutrient sensing machinery, although its role in these complexes remains unclear. More recently, the PDRG1 protein was found as an interaction target for the catalytic subunits of methionine adenosyltransferases. These enzymes synthesize S-adenosylmethionine, the methyl donor for, among others, epigenetic methylations that occur on the DNA and histones. In fact, downregulation of S-adenosylmethionine synthesis is the first functional effect directly ascribed to PDRG1. The existence of global DNA hypomethylation, together with increased PDRG1 expression, in many tumor cells highlights the importance of this interaction as one of the putative underlying causes for cell transformation. Here, we will review the accumulated knowledge on this oncogene, emphasizing the numerous aspects that remain to be explored.

Gankyrin: A potential target for drug therapy against hepatocellular carcinoma

Hepatocellular Carcinoma is a primary malignant tumor of the liver and gankyrin is an oncoprotein over-expressed in hepatocellular carcinoma. It has been found that Gankyrin protein reduces the level of p53 protein by increasing its ubiquitylation and degradation, following a MDM-2 mediated pathway. Interaction of gankyrin with MDM2 enhances the ubiquitylation of p53. Independent study of this protein molecule revealed that it is identical to the p28 subunit of the 26S proteasome, having seven similar alpha helical ankyrin repeats. Gankyrin also binds to the Tumor Suppressor Protein (TSP) Retinoblastoma (RB), thereby accelerating its phosphorylation and proteasomal degradation. Blocking the expression of Gankyrin with MDM2 in cases of Hepatocellular Carcinoma (HCC) promoted apoptosis in cancer cells. Hence, Gankyrin can be used as a potential target for drug therapy against Hepatocellular Carcinoma.

Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS

Human cancers typically express a high level of tumor-promoting mutant p53 protein(Mutp53)with a minimal level of tumor-suppressing wild-type p53 protein(WTp53).In this regard,inducing Mutp53 degradation while activating WTp53 is a viable strategy for precise anti-tumor therapy.Herein,a new carrier-free nanoprodrug(i.e.,Mn-ZnO_(2)nanoparticles)was developed for concurrent delivery of dual Zn-Mn ions and reactive oxygen species(ROS)within tumor to regulate the p53 protein for high anti-tumor efficacy.In response to the mild tumor acidic environment,the released Zn^(2+)and H_(2)O_(2)from Mn-ZnO_(2)NPs induced ubiquitination-mediated proteasomal degradation of Mutp53,while the liberative Mn^(2+)and increased ROS level activated the ATM-p53-Bax pathway to elevate WTp53 level.Both in vitro and in vivo results demonstrated that pH-responsive decomposition of Mn-ZnO2 NPs could effectively elevate the intracellular dual Zn-Mn ions and ROS level and subsequently generate the cytotoxic hydroxyl radical(·OH)through the Fenton-like reaction.With the integration of multiple functions(i.e.,carrier-free ion and ROS delivery,tumor accumulation,p53 protein modulation,toxic·OH generation,and pH-activated MRI contrast)in a single nanosystem,Mn-ZnO_(2)NPs demonstrate its superiority as a promising nanotherapeutics for p53-mutated tumor therapy.