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The p53 protein is an essential tumor suppressor in the human body that plays a critical role in preventing tumor formation by controlling cell cycle arrest and promoting apoptosis. Mutations in the p53 gene are frequently observed in more than 50% of tumor tissues and lead to the generation of mutant p53 proteins, which not only have a dominant-negative effect (DN) that hinders the function of wild-type p53 protein but also have gain-of-function (GOF) effects that stimulate tumor development by regulating cell metabolism, invasion, migration, and other processes. Therefore, mutant p53 protein has become a specific drug target for cancer therapy. However, the lack of a drug-binding pocket and smooth surface of mutant p53 proteins have made them undruggable targets for a long time. In recent years, with the development of high-throughput screening technology and an enhanced understanding of the structure and conformational changes exhibited by mutant p53 proteins, a multitude of small molecule compounds directed against mutant p53 protein have been identified, exhibiting substantial in vitro anti-tumor efficacy. Moreover, some of these compounds have entered clinical trials. This review summarized the direct and indirect strategies for the treatment of cancers targeting mutant p53, with a primary focus on the mechanisms of action of small molecule compounds that reactivate mutant p53 protein or degrade mutant p53 protein. The aim is to provide assistance for the development of innovative drugs targeting mutant p53 protein in the future.
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Tumor suppressor p53 protein can regulate the tran-scription of target genes, to control cell apoptosis, aging and other life activities,but mutant p53 is prone to losing antitumor function, thus promoting tumor development. At present, p53 protein has become one of the hot targets for the treatment of cancer. This article mainly introduces the structure and mechanism of small molecular compounds with restoring activity of mutant p53 as the target.
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Objective To investigate the clinicopathological significances of LDHA/mutant p53 co-expres-sion in gliomas. Methods According to the 2016 WHO CNS,archived 68 gliomas were collected and analyzed retrospectively. The co-expression of LDHA/mutant p53 was detected by immunohistochemical staining. Results High expression of LDHA alone was always found in high grade gliomas(48.5%). Mutant p53 high expression was usually observed in glioblastomas (26.5%). There was a close relationship between co-expression of LDHA/mutant p53 in glioblastoma(27.9%,P = 0.005),or gliomas with high histological grading(27.9%,P = 0.002). Conclusions Co-expression of LDHA/mutant p53 in tumor cells might be a specific immunohistochemical pheno-type of gliomas,and may help for distinguishing glioblastoma and other high grade gliomas from low grade gliomas.
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Objective To investigate the expression and prognostic significance of P-JAK2, P-STAT3 and mutant p53 in cervical lesions. Methods A total of 153 cervical biopsies of patients from Gynecology Department, The Second Hospital of Tianjin Medical University were recruited during December 2013 to June 2015. Fifty-seven cases of squamous carcinoma of cervix (SCC), 36 cases of low grade intraepithelial neoplasia (LSIL), 30 patients with high grade intraepithelial neoplasia (HSIL) and 30 cases of normal cervix (NC) were included in the study. Gene chip method was used to detect high-risk hu-man papillpmavirus(HR-HPV)infection. Hematoxylin-eosin staining was used to make pathological diagnosis. Immunohis-tochemical assay was used for the detection of P-JAK2, P-STAT3 and mutant type p53 protein expression in cervical le-sions. Results (1) HR-HPV infection rate and P-JAK2 expression were significantly higher in SCC group than those of HSIL group, LSIL group and NC group (P<0.05). (2) The expression of P-STAT3 and mutant type p53 were significantly higher in SCC group than those of LSIL group and NC group (P<0.05). However, there was no significant difference between SCC group and HSIL group. (3) The positive expressions of P-JAK2 and P-STAT3 showed significant differences in different FIGO stages, histopathological grade, lymph node metastasis and HR-HPV infection in SCC group, respectively ( P<0.05). There were significant differences in the positive expression of mutant type p53 between different FIGO stages and HR-HPV infection (P<0.05). (4) There was positive correlation between P-JAK2, P-STAT3, positive expression of mutant type p53 and HR-HPV infection in SCC tissues (P<0.05). There was a positive correlation between P-STAT3, p53 expression and HR-HPV infection (P<0.05). There was a positive correlation between mutant p53 expression and HR-HPV infection (P<0.05). Conclusion P-JAK2, P-STAT3 and mutant p53 protein expression rates are high in SCC group than those of NC and SIL groups, which may be associated with HR-HPV infection, cervical cancer occurrence and progression.
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Objective:To detect precancerous lesions of gastric cancer and biopsy tissue vascular endothelial growth factor (VEGF)and mutant p53 gene(mtp53)expression,to explore the development of clinical significance of VEGF and mutant p53 gene in gastric cancer.Methods:19 cases by endoscopic biopsies of normal gastric tissues,22 cases of intestinal metaplasia,47 cases of gastro-intestinal mucosal dysplasia, 54 cases of gastric cancer samples by immunohistochemical staining to detect the expression levels of VEGF and mtp53′s.Results: The expression levels of VEGF, mtp53 in normal gastric mucosa, intestinal metaplasia, dysplasia, and gradually increased gastric cancer was the law.mtp53 of VEGF expression in gastric carcinoma and compared with normal gastric tissue,intestinal metaplasia was significantly higher(P0.05). Conclusion: The abnormal expression of VEGF and mutant p53 may be related to the degree of deterioration of the stomach tissue lesions related.
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Notch1 has been reported to be highly expressed in triple-negative and other subtypes of breast cancer. Mutant p53 (R280K) is overexpressed in MDA-MB-231 triple-negative human breast cancer cells. The present study aimed to determine whether the mutant p53 can be a potent transcriptional activator of the Notch1 in MDA-MB-231 cells, and explore the role of this mutant p53-Notch1 axis in curcumin-induced apoptosis. We found that curcumin treatment resulted in an induction of apoptosis in MDA-MB-231 cells, together with downregulation of Notch1 and its downstream target, Hes1. This reduction in Notch1 expression was determined to be due to the decreased activity of endogenous mutant p53. We confirmed the suppressive effect of curcumin on Notch1 transcription by performing a Notch1 promoter-driven reporter assay and identified a putative p53-binding site in the Notch1 promoter by EMSA and chromatin immunoprecipitation analysis. Overexpression of mutant p53 increased Notch1 promoter activity, whereas knockdown of mutant p53 by small interfering RNA suppressed Notch1 expression, leading to the induction of cellular apoptosis. Moreover, curcumin-induced apoptosis was further enhanced by the knockdown of Notch1 or mutant p53, but it was decreased by the overexpression of active Notch1. Taken together, our results demonstrate, for the first time, that Notch1 is a transcriptional target of mutant p53 in breast cancer cells and suggest that the targeting of mutant p53 and/or Notch1 may be combined with a chemotherapeutic strategy to improve the response of breast cancer cells to curcumin.
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Humanos , Apoptosis , Vértebra Cervical Axis , Mama , Neoplasias de la Mama , Inmunoprecipitación de Cromatina , Curcumina , Regulación hacia Abajo , ARN Interferente PequeñoRESUMEN
Objective To study the association between cytotoxin-associated gene A of Helicobacter pylori (Hp-CagA) and the expressions of mtp53 and c-myc protein in different subtypes of intestinal metaplasia.Methods One hundred and sixty-five patients with gastroscopy included 125 cases with chronic atrophic gastritis with intestinal metaplasia,40 cases with non-atrophic gastritis.Intestinal metaplasia included complete intestinal metaplasia,incompletetype intestinal metaplasia,complete colonic epithelial metaplasia and incomplete colonic epithelial metaplasia.The carbon-14-urea breath test was used to determine Helicobacter pylori (Hp);AB-PAS and HID-AB mucinous staining was used to distinguish intestinal metaplasia subtypes; the immunohistochemical Elivision method was used to determine the expressions ofmtp53 and c-myc protein;indirect ELISA was used to determine Hp-CagA.Results Forty-five cases with incomplete colonic epithelial metaplasia,47 cases with incomplete type intestinal metaplasta,17 cases with complete colonic epithelial metaplasia,16 cases with complete intestinal metaplasia.The positive rate of Hp-CagA in all intestinal metaplasia subtypes was higher than that in non-atrophic gastritis,but there was no significant difference (P ＞ 0.05).The expression of mtp53 protein in incomplete colonic type of intestinal metaplasia with Hp-CagA positive was higher than that in incomplete colonic type of intestinal metaplasia with Hp-CagA negative (x2 =5.494,P ＜ 0.05).The expression of c-myc protein in incomplete colonic type of intestinal metaplasia with Hp-CagA positive was higher than that in incomplete colonic type of intestinal metaplasia with Hp-CagA negative (x2 =13.950,P ＜ 0.01).Conclusion Hp-CagA is a sort of highly virulent strain,and Hp-CagA may do a strong role in the promotion of gastric atrophy and intestinal metaplasia.
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Objective To determine whether HBx gene can directly induce hepatocellular carcinoma in vivo, and to explore the mechanism of transplantation tumor in nude mice.Methods pCMVX/QSG7701 cell lines were vaccinated into subcutaneous tissue of nude mice. pRcCMV2/QSG7701 and QSG7701 cell lines were used as controls. The sections of transplantation tumor were observed microscopically by HE staining. RT-PCR was used to detect the expression of mutant p53 and c-Myc mRNA in transplant tumor and an other 3 cell lines. Results The transplant tumor occurred within the subcutaneous tissue of the nude mice inoculated with pCMVX/QSG7701 cell lines at 2nd week after the vaccination. No metastatic tumor was found in other organs. Transplant tumor was not formed in all the controls. HE staining confirmed that the transplant tumor was hepatocellular carcinoma. The mutant p53 mRNA and c-Myc mRNA expression level of transplant tumor and pCMVX/QSG7701 cells was significantly higher than that of pRcCMV2/QSG7701 and QSG7701 cells, respectively (P＜0.01).Conclusion HBx gene can up-regulate the expression of mutant p53 and c-Myc genes, and directly induce hepatocellular carcinoma in vivo.
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Objective To detect the expression of apurinic/apyrimidinic endonuclease 1 (APEI) and explore its correlation with the expression of mutant p53 in hepatocellular carcinoma (HCC). Methods The expression of APE1 and mutant p53 was detected by SP immunohistochemical method in 10 specimens of normal liver tissue, 40 specimens of liver cirrhosis tissue and 103 specimens of HCC tissue which were collected at the Department of Pathology of Daping Hospital from 1991 to 2004. All data were analyzed by chi-square test, correla-tion analysis and K Independent-Samples Tests. Results The expression rate of APE1 in HCC was 100.0%, which was significantly higher than that in normal liver tissue (40.0%) and liver cirrhosis tissue (82.5%) (χ~2= 47.852, P < 0.01). The expression of APE1 was only detected in the nucleus in normal liver tissue. Ectopic expression of APE1 in cytoplasm was detected in liver cirrhosis tissue and HCC tissue, with the rate of 20.0% and 53.4%, respectively (χ~2=20.757, P <0.01). There was statistical difference in clinical staging and pathological grading of HCC with different combinations of APE1 expression (intranuclear or ectopic expression) and mutant p53 expression (positive or negative expression) (χ~2=12.910, 14.481, P < 0.01), and HCC with ectopic expression of APE1 and positive expression of p53 had high malignant degree. Conclusion Overexpression and ectopic expression of APE1 in cytoplasm may play important roles in the genesis and progression of HCC, and the ectopic expression of APE1 and p53 mutation may have synergistic effect.
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Radiation therapy is one of the most important treatment modalities following surgery of the primary malignant or metastatic brain tumors. But radiation can be harmful to normal healthy brain tissues around the tumor. There have been numerous reports of radiation induced damage such as delayed necrosis to human brain after therapeutic exposure. Apoptosis is a form of cell death with morphological and biochemical features that differ from those of necrosis. The aim of this study is to evaluate the apoptosis in normal rat brain after irradiation. Twenty one Sprague-Dawley rats were given a single dose of 10 Gy using high dose rate Ir-192 over 5 minutes at the right frontal region. Apoptosis was evaluated by the TUNEL method(In-situ end labelling technique) and mutant p53 protein, bc1-2 and bax genes were evaluated by immunohistochemical stain. Apoptosis was assessed at 1 week(group A, n=5), 2 week(group B, n=), 4 week(group C, n=), 6 week(group D, n=), 8 week(group E, n=) after irradiation. Apoptosis was noted with 20% of cases(1/5) in group A, 40% of cases(2/5) in group B, 60% of cases(3/5) in group C, 67% of cases(2/3) in group D and 100% of cases(3/3) in group E. Overall apoptosis positive rate was 52.4%(11/21). Apoptosis was most prominently found in external granular and external pyramidal layer(82%, 9/11) and found one case in internal pyramidal layer and the other one case in corticowhite matter junction. There were no positive stainning for mutant p53 protein, bc1-2 and bax gene in all cases pertaining to the phenomenon of apoptosis. In conclusion, apoptosis was evident in the rat brain after irradiation and the incidence of apoptosis was increased with time after irradiation. But the genes related to apoptosis after irradiation were not apparent in this study. Further evaluation including biochemical and clonogenic study needs to clarify the mechanism of apoptosis in normal brain after irradiation.
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Animales , Humanos , Ratas , Apoptosis , Neoplasias Encefálicas , Encéfalo , Muerte Celular , Etiquetado Corte-Fin in Situ , Incidencia , Necrosis , Ratas Sprague-DawleyRESUMEN
PURPOSE: MAGE (melanoma antigen gene) is a tumor associated antigen, presented by HLA class I molecules, which is recognized by cytotoxic T lymphocytes. The expression of MAGE proteins are confined to malignant tumor tissues, except for the normal testis and placental tissues. Therefore, MAGE may be a potential target for immunotherapy of malignant tumors. However, biological aspects associated with the cell cycle are not yet described. MATERIALS AND METHODS: The material used for this study was a novel human squamous cell carcinoma cell line (PNUH-12) from the hypopharynx, which had one point mutation of 78th base, C to G, in exon 7 of p53 gene. To understand the role of MAGE in relation to cell cycle and its relationship with p53 as the Gl checkpoint regulator, the expressions of MAGE-3 protein and mvtant p53 (Mtp53) were accessed by flow cytometry and immunohistochemistry. Double stains for MAGE-3/Mtp53 was analyzed with bivariate flow cytometry. DNA histograms using MAGE-3/PI (DNA) and Mtp53/PI (DNA) were also analyzed. RESULTS: The expression rate of MAGE-3 and Mtp53 were 83% and 85%, respectively. MAGE-3 was expressed in cytoplasm, while M:p53 were expressed in the nuclei of the tumor cells on the immunohistochemical sections. With bivariate analyses, coexpression rate of MAGE-3/Mtp53 was 0.96, and MAGE-3 and Mtp53 constantly showed high levels throughout the cell cycle except Go. CONCLUSIONS: These results mean that (I) MAGE-3 might have yet unknown relationship with mutant p53, (2) expressions of MAGE-3 and Mtp53 are not dependent on the cell cycle in PNUH-12 hypopharyngeal squamous carcinoma cell line, and suggest that MAGE-3 might have a role as important as p53 during the development of malignant tumors.
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Humanos , Carcinoma de Células Escamosas , Ciclo Celular , Línea Celular , Colorantes , Citoplasma , ADN , Exones , Citometría de Flujo , Genes p53 , Hipofaringe , Inmunohistoquímica , Inmunoterapia , Mutación Puntual , Linfocitos T Citotóxicos , TestículoRESUMEN
PURPOSE: The significance of constitutive apoptosis in the development and progression of transitional ceil carcinoma of the bladder has yet to be investigated. The wild type p53 gene is known to play a significant role in apoptosis. Therefore, mutation of p53 gene, which correlates closely with p53 protein overexpression, would be predicted to limit apoptosis. We evlauated the prognostic significance of apoptosis and the relationship between apoptosis and mutant p53 overexpression in transitional cell carcinoma of bladder. MATERIALS AND METHODS: The extent of apoptosis was determined by TUNEL(terminal deoxynucleotidyl transferase mediated biotinylated deoxyuridine-triphosphate nick end labeling) stain in 64 paraffin embedded tissue of primacy transitional cell carcinoma specimens. Also, the level of p53 overexpression was determined immunohistochemically on the same tissue. RESULTS: Although the incidence of apoptosis increased with increasing tumor grade, the difference in indices between grade II and grade III failed to reach statistical significance. The mean apoptotic index(AI) of grade I tumors was significantly lower than that of grade III tumors(p=0.0023). The apoptotic index was not related to p53 overexpression, T(tumor)-category, growth type of tumors and also there was no significant difference in disease-free survival between the bladder tumors with high as opposed to low apoptotic index. CONCLUSIONS: The results show that AI is related to histological grade in transitional cell bladder tumor, while AI hardly has any independent prognostic significance.
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Apoptosis , Carcinoma de Células Transicionales , Supervivencia sin Enfermedad , ADN Nucleotidilexotransferasa , Genes p53 , Incidencia , Parafina , Neoplasias de la Vejiga Urinaria , Vejiga UrinariaRESUMEN
BACKGROUND: Expression of mutant p53 has been observed in a variety of human cancers, including head and neck squamous cell carcinoma and carcinoma of breast, colon, esophagus, lung, stomach, liver, thyroid, etc. OBJECTIVES: To establish expression frequency of p53 and correlation between p53 expression and clinicopathologic data in squamous cell carcinoma of head and neck. MATERIALS AND METHODS: Fresh tissue samples were obtained from 66 patients with squamous cell carcinoma of head and neck undergoing biopsy or surgery. Expression of mutant p53 was evaluated by immunohistochemical staining with anti-p53 monoclonal antibody in 66 paraffin-embedded tissues of squamous cell carcinoma in head and neck. The studies consisted of 13 cases of oral carcinoma including tongue, 10 cases of pharyngeal carcinoma and 43 cases of laryngeal carcinoma. RESULTS: 1) The frequency of p53 expression in squamous cell carcinoma of head and neck was 48.5%((31/66). 2) The frequency of p53 expression by tumor site was 42.6%(6/13) in oral cavity, 60%(6/10) in pharynx and 44.2%(19/43) in larynx. 3) A positive relationship was seen between p53 expression and lymphnode metastasis, representing 69.2% p53 expression in metastasis group and 16.7% p53 in non-metastasis group. CONCLUSION: Author was suggested that p53 expression in squamous cell carcinoma of head and neck was related to tumor progression and metastasis.
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Humanos , Biopsia , Mama , Carcinoma de Células Escamosas , Colon , Esófago , Cabeza , Laringe , Hígado , Pulmón , Boca , Cuello , Metástasis de la Neoplasia , Faringe , Estómago , Glándula Tiroides , LenguaRESUMEN
The epidemiology of cancer has long been suggested that cancer is multistep disease. We suspect some of these steps might be lated with activation of oncogenes and loss of tumor suppressor genes in primary brain tumors. Moreover, recent reports suggest that astrocytomas have shown alterations in chromosome 17p, and this chromosomal location that encodes the p53 protein, as well as c-fos gene may take an important role in the carcinogenesis of human primary brain tumors. Expression of p53 protein was detected in 12 of 17 cases(70.6%) of glioblastoma multiforme, 4 of 6 cases(66.6%) of anaplastic astrocytoma with positive nuclear p53 staining. All low grade astrocytomas and normal brain tissue failed to express p53. Correlation of p53 protein levels with mRNA alterations or genomic DNA alterations may help to guide future therapy or diagnosis of brain tumors. On the other hand, the level of c-fos oncoprotein expression may be correlated with the degree of cell differentiation and proliferation. The presence of these expression in low-grade astrocytoma suggest that activation of the c-fos gene is an early step in tumor development.
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Humanos , Astrocitoma , Neoplasias Encefálicas , Encéfalo , Carcinogénesis , Diferenciación Celular , Diagnóstico , ADN , Epidemiología , Genes fos , Genes Supresores de Tumor , Glioblastoma , Glioma , Mano , Inmunohistoquímica , Oncogenes , ARN MensajeroRESUMEN
AIM:To explore the effect and significance of neuregulins /ErbB2 receptor signal transduction pathway on mtp53 and hypoxia-iducible factor-1?(HIF-1?) in none-overexpression ErbB2 breast cancer cell MDA-MB-231.METHODS:The expression of neuregulin was detected by immunocytochemistry and Western blotting.MDA-MB-231 cells were treated with ErbB2 kinase inhibitor AG825.Proliferation was measured by MTT assay.The cell cycle and apoptosis were determined by flow cytometry.The expressions of mtp53 and HIF-1? were detected by Western blotting.The mRNA expression of HIF-1? was detected by RT-PCR.RESULTS:MDA-MB-231 cells expressed a relative higher level of neuregulin.In the results of Western blotting,the positive reaction band was found in 44 kD which coincides with the molecular weight of neuregulin.When MDA-MB-231 cells were treated with AG825,the proliferation was inhibited in time and dose dependent manners(P