DNA double-stranded break (DSB) is one of the most catastrophic damages of genotoxic insult. Inappropriate repair of DNA DSBs results in the loss of genetic information, mutation, and the generation of harmful genomic rearrangements, which predisposes an organism to immunodeficiency, neurological damage, and cancer. The tumor repressor p53 plays a key role in DNA damage response, and has been found to be mutated in 50% of human cancer. p53, p63, and p73 are three members of the p53 gene family. Recent discoveries have shown that human p53 gene encodes at least 12 isoforms. Different p53 members and isoforms play various roles in orchestrating DNA damage response to maintain genomic integrity. This review briefly explores the functions of p53 and its isoforms in DNA DSB repair.
Animals ; DNA Breaks, Double-Stranded ; DNA Repair ; Humans ; Mice ; Protein Isoforms ; physiology ; Tumor Protein p73 ; physiology ; Tumor Suppressor Protein p53 ; genetics ; physiology

Ovarian cancer is the leading cause of death in women worldwide. Cisplatin is the core of first-line chemotherapy for patients with advanced ovarian cancer. Many patients eventually become resistant to cisplatin, diminishing its therapeutic effect. MicroRNAs (miRNAs) have critical functions in diverse biological processes. Using miRNA profiling and polymerase chain reaction validation, we identified a panel of differentially expressed miRNAs and their potential targets in cisplatin-resistant SKOV3/DDP ovarian cancer cells relative to cisplatin-sensitive SKOV3 parental cells. More specifically, our results revealed significant changes in the expression of 13 of 663 miRNAs analyzed, including 11 that were up-regulated and 2 that were down-regulated in SKOV3/DDP cells with or without cisplatin treatment compared with SKOV3 cells with or without cisplatin treatment. miRNA array and mRNA array data were further analyzed using Ingenuity Pathway Analysis software. Bioinformatics analysis suggests that the genes ANKRD17, SMC1A, SUMO1, GTF2H1, and TP73, which are involved in DNA damage signaling pathways, are potential targets of miRNAs in promoting cisplatin resistance. This study highlights candidate miRNA-mRNA interactions that may contribute to cisplatin resistance in ovarian cancer.
Cell Cycle Proteins ; Cell Line, Tumor ; Chromosomal Proteins, Non-Histone ; Cisplatin ; Cysteine Endopeptidases ; DNA-Binding Proteins ; Down-Regulation ; Drug Resistance, Neoplasm ; Endopeptidases ; Female ; Humans ; MicroRNAs ; Nuclear Proteins ; Ovarian Neoplasms ; Phosphoproteins ; RNA, Messenger ; Signal Transduction ; Transcription Factors, TFII ; Tumor Protein p73 ; Tumor Suppressor Proteins ; Up-Regulation

OBJECTIVETo investigate the mRNA expression and promoter methylation status of p73 gene in the peripheral blood of children with Wilms' tumor (WT), and their relationship.

METHODSForty-five children with WT were selected as the case group, and 15 sex- and age- matched children (without malignancies) who visited the hospital for physical examination or other reasons were selected as the control group. Peripheral blood was collected from both groups. Real-time quantitative PCR and methylation-specific PCR were used to determine the mRNA expression level and promoter methylation status of p73 gene. Their relationship with clinicopathological features and the effect of promoter methylation on mRNA expression of p73 gene were analyzed in the case group.

RESULTSThe relative quantity (RQ) of p73 mRNA in the case group was significantly higher than in the control group (3.2 ± 0.9 vs 1.6 ± 1.1; P<0.01). The positive rate of p73 gene promoter methylation in the case group was significantly lower than in the control group (20% vs 73%; P<0.01). In the case group, the RQ of p73 mRNA was significantly higher in children with methylated p73 gene promoter than in those with unmethylated p73 gene promoter (P<0.01). In children with methylated p73 gene promoter, the RQ of p73 mRNA was significantly higher in the case group than in the control group (P<0.01). In children with unmethylated p73 gene promoter, there was no significant difference in RQ of p73 mRNA between the case and control groups (P=0.810).

CONCLUSIONSAberrant promoter methylation of p73 gene in peripheral blood is one of the gene expression regulations in children with WT, and it is related to the onset and development of WT. The p73 gene may play a role as oncogene in WT patients with p73 gene promoter methylation and mRNA overexpression is associated with promoter methylation status of p73 gene.

Child, Preschool ; DNA Methylation ; DNA-Binding Proteins ; genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Infant ; Kidney Neoplasms ; genetics ; Male ; Nuclear Proteins ; genetics ; Promoter Regions, Genetic ; RNA, Messenger ; blood ; Tumor Protein p73 ; Tumor Suppressor Proteins ; genetics ; Wilms Tumor ; genetics

OBJECTIVETo study the methylation status of p73 gene promoter in patients with myelodysplastic syndrome (MDS) and explore its significance with clinical prognosis.

METHODSMethylation of p73 promoter was detected in bone marrow cells from 135 MDS patients and 13 healthy controls by methylation-specific PCR (MSP). The results of MSP were confirmed by bisulfite sequencing. The expression of p73 mRNA was detected by real-time quantitative PCR. Primary bone marrow cells from MDS patients were treated with decitabine, the changes of p73 methylation status and p73 mRNA expression were measured. The role of p73 methylation in the prognosis of MDS and the correlated clinical data were explored.

RESULTSp73 hypermethylation was present in 37.04% of MDS cases and patients with high risk MDS (RAEB-1 and RAEB-2) exhibited a significantly higher frequency of p73 methylation than that of low risk MDS (58.8% vs 29.7%, P = 0.002). The expression of p73 mRNA in the methylated group was decreased compared to that of the unmethylated group (P = 0.032). Decitabine treatment decreased the level of p73 methylation and increased the level of p73 transcripts. Patients with p73 methylation progressed rapidly to AML (P < 0.001) and had shorter survival (P = 0.002) than those who did not have p73 methylation. In the multivariate Cox regression model, BM blast and p73 methylation status emerged as independent prognostic factor for overall survival and leukemia free survival.

CONCLUSIONp73 gene methylation is common in patients with MDS and may indicate poor prognosis. p73 may be a therapeutic target in MDS.

Aged ; Case-Control Studies ; DNA Methylation ; DNA-Binding Proteins ; genetics ; Female ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes ; genetics ; Nuclear Proteins ; genetics ; Prognosis ; Promoter Regions, Genetic ; Tumor Protein p73 ; Tumor Suppressor Proteins ; genetics

OBJECTIVETo investigate the expression and promoter methylation status of p73 gene in ovarian epithelial tumors and their clinicopathological correlations.

METHODSTissue microarrays (TMA) consisting of 68 ovarian cancers, 37 ovarian borderline tumors and 21 ovarian benign tumors were constructed. p73 expression was detected by immunohistochemistry (EnVision method). Fresh-frozen tissue samples from 13 cases of ovarian carcinomas and 5 cases of borderline tumors were evaluated for the presence of p73 promoter methylation using bisulfite sequencing.

RESULTSOverall, 92.6% (63/68) ovarian carcinomas expressed p73, with a mean value of 32% (percentage of p73 positive cells in the tumor). The mean value of p73 expression rate (40%) in serous carcinoma (26/26) was higher than those of other cancer types (P = 0.006). The mean value of p73 expression rate (40%) in type II ovarian carcinoma was significantly higher than that in type I ovarian carcinoma (24%, P = 0.010). The expression of p73 was not associated with FIGO stage and histological grade (both P > 0.05). The mean values of p73 expression in ovarian borderline tumor (30/37) and benign tumor (12/21) were 16% and 15%, respectively. Of the two groups, the mean value of p73 expression rate in serous type was higher than that in mucous type (P = 0.003, P = 0.026). Ovarian carcinomas had a higher level of p73 expression than borderline tumors and benign tumors (both P < 0.05), while that between ovarian borderline tumors and benign tumors had no statistical difference (P > 0.05). Among serous tumors (49/53), the mean value of p73 expression in the carcinoma group (26/26) was significantly higher than those in the borderline tumor group (12/14) and benign tumor group (11/13; P = 0.024 and P = 0.002, respectively), while that between borderline tumor group and benign tumor group had no statistical difference (P = 0.428). Among mucous tumors (15/27), the mean value of p73 expression in carcinoma group (6/7) was higher than that in benign tumor group (1/8; P = 0.032). No statistical difference of p73 expression was seen between the carcinoma group and ovarian borderline tumor group (8/12) and between the borderline tumor group and benign tumor group (P = 0.234, P = 0.201, respectively). p73 promotor methylation was found in 8 of 13 cases of carcinomas but at different methylation levels with a mean value of 8.0%. Two of 5 ovarian borderline tumors showed detectable p73 promotor methylation with a mean value of 9.0%. Compared with the borderline tumors, ovarian carcinomas showed a similar p73 methylation level (P > 0.05). The p73 methylation level in ovarian carcinomas was not associated with histological type, pathogenetic type, histological grade and FIGO stage (all P > 0.05).

CONCLUSIONSMost of ovarian epithelial tumors express p73 protein with mean values higher in ovarian carcinomas than those in the borderline and benign tumors. Ovarian serous carcinomas have the highest expression level of p73. A simple linear correlation does not exist between the promoter methylation and protein expression of p73.

Adult ; Aged ; Cystadenocarcinoma, Mucinous ; metabolism ; pathology ; Cystadenocarcinoma, Serous ; metabolism ; pathology ; Cystadenofibroma ; metabolism ; pathology ; Cystadenoma, Mucinous ; metabolism ; pathology ; Cystadenoma, Serous ; metabolism ; pathology ; DNA Methylation ; DNA-Binding Proteins ; metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Neoplasms, Glandular and Epithelial ; metabolism ; pathology ; Nuclear Proteins ; metabolism ; Oligonucleotide Array Sequence Analysis ; Ovarian Neoplasms ; metabolism ; pathology ; Promoter Regions, Genetic ; Tumor Protein p73 ; Tumor Suppressor Proteins ; metabolism ; Young Adult

OBJECTIVE: To evaluate the correlations between p73 G4C14-A4T14 polymorphisms and clinicopathologic characteristics of patients with breast cancer. METHODS: A total of 170 patients with breast cancer were genotyped for p73 G4C14-A4T14 polymorphisms by Sequenom MassArray® iPLEX GOLD System. The correlations between polymorphisms and the age of patients with breast cancer, or tumor size were analyzed by t-test;the correlations between polymorphisms and clinicopathologic characteristics in patients with breast cancer were analyzed by Χ(2) test; and the relation between polymorphisms and the efficacy of chemotherapy for breast cancer was assessed by logistic regression. RESULTS: There was negative correlation between p73 polymorphisms and ser veral clinicopathological characteristics, including age, tumor size, menopausal status, TNM classification, pathological type, axillary lymph node metastasis, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and p53(P>0.05). The frequency of GC/GC genotype in patients with "triple negative" breast cancer (estrogen receptor -negative, progesterone receptornegative, and human epidermal growth factor receptor 2-negative) was higher than that of patients with non-triple negative breast cancer (78.9% vs 57.6%, Χ(2)=5.741, P=0.017). P73 polymorphism was negatively correlated with chemosensitivity for anthracycline-based chemotherapy (P>0.05). CONCLUSION P73 G4C14-A4T14 polymorphisms are positively correlated with triple negative breast cancer, and the patients with breast cancer who carry GC/GC genotype may have bad prognosis.
Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms ; genetics ; metabolism ; pathology ; DNA-Binding Proteins ; genetics ; Female ; Genotype ; Humans ; Middle Aged ; Nuclear Proteins ; genetics ; Polymorphism, Genetic ; Receptor, ErbB-2 ; metabolism ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism ; Tumor Protein p73 ; Tumor Suppressor Proteins ; genetics

BACKGROUNDp73, a homologue of p53, has been located at chromosome 1p36-33, a region of frequently observed loss of heterozygosity in breast cancers. The objective of the present study was to investigate the function of p73 in Japanese with breast cancers.

METHODSSixty Japanese patients with breast cancer were assessed by polymerase chain reaction single strand confirmation polymorphism analysis and direct sequencing to detect the p73 allele. p73 mRNA levels were also determined in 40 out of 60 patients by reverse-transcriptional polymerase chain reaction.

RESULTSWe analyzed the entire open reading frame of the p73 gene by polymerase chain reaction single strand confirmation polymorphism and sequencing, and failed to identify any mutations of p73 in the encoding regions detected. Loss of heterozygosity of p73 was infrequent and only found in 9% of breast carcinomas. We revealed a few polymorphisms with a frequency of 13% - 29%, which had been reported previously. Down-regulation of p73 mRNA expression was observed in tumor tissues in comparison to the normal breast tissues. A significant inverse correlation was found between p73 transcripts and high histological grade, suggesting that down-regulated p73 expression could be related to poor prognosis in those patients.

CONCLUSIONOur results suggest that p73 may serve as a tumor suppressor gene and its expression plays a role in tumorigenesis in Japanese patients with breast cancer.

Breast Neoplasms ; genetics ; metabolism ; pathology ; Carcinoma ; genetics ; metabolism ; pathology ; DNA-Binding Proteins ; genetics ; Female ; Humans ; Loss of Heterozygosity ; genetics ; Middle Aged ; Nuclear Proteins ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Protein p73 ; Tumor Suppressor Protein p53 ; genetics ; metabolism ; Tumor Suppressor Proteins ; genetics

OBJECTIVE: To study the clinical significance of the expression of p53, p63 and p73 protein and the correlation of p53 and p63 in nasal and paranasal sinus carcinoma (NPSC). METHOD: The immunohistochemical technique was used to detect the expression of p53, p63 and p73 in 67 cases of NPSC, para-cancer tissues and non-cancer tissues. RESULT: The positive rate of p53 and p63 protein in NPSC was significantly higher than that in park cancer tissues and non-cancer tissues (P<0.01), and there were a positive correlation between the expression of p53 and p63 protein in NPSC (P<0.01). But the expression of p73 had no significant difference among NPSC, para-cancer tissues and non-cancer tissues (P>0.05). CONCLUSION There are positive correlation between p53 and p63 protein in NPSC, and they may play an important role in the tumorgenesis of NPSC. The p73 may not be associated with tumorgenesis of NPSC.
Carcinoma, Squamous Cell ; metabolism ; pathology ; DNA-Binding Proteins ; metabolism ; Female ; Humans ; Male ; Middle Aged ; Nose Neoplasms ; metabolism ; pathology ; Nuclear Proteins ; metabolism ; Paranasal Sinus Neoplasms ; metabolism ; parasitology ; Trans-Activators ; metabolism ; Transcription Factors ; Tumor Protein p73 ; Tumor Suppressor Protein p53 ; metabolism ; Tumor Suppressor Proteins ; metabolism

OBJECTIVEIt has been proposed that genetic polymorphisms in apoptosis-related genes might be associated with sensitivity of cancer cells to platinum-based chemotherapy. This study examined the relationship between p53 and p73 genetic polymorphisms and the response to platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).

METHODSA total of 165 patients with advanced NSCLC treated with platinum-based chemotherapy were genotyped for the p53 codon 72 Pro-->Arg and p73 exon 2 G4C14-->A4T14 polymorphisms using PCR-RFLP and ARMS-PCR assays. Clinical response to the chemotherapy was obtained after 2 to 3 cycles. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression model. All statistical tests were two-sided.

RESULTSThe p53 Pro allele carriers had higher response rate than non-carriers (OR = 2.46; 95% CI = 1.11 - 5.45). A higher response rate was also observed for the p73 G4C14/A4T14 or A4T14/A4T14 genotype, compared with the G4C14/G4C14 genotype (OR = 2.22; 95% CI = 1.14 - 4.30). When these two polymorphisms were combined to be analyzed, it was found that the response rate in those carrying the wild-type genotypes at both genes was only 7.7%, whereas the response rates in patients carrying 1, 2, or more than 2 variant alleles of p53 and p73 were 34.8%, 42.2% and 40.7%, respectively.

CONCLUSIONThose results suggest that p53 and p73 polymorphisms may be associated with clinical responsiveness to platinum-based chemotherapy in advanced NSCLC.

Adult ; Aged ; Antineoplastic Agents ; therapeutic use ; Carboplatin ; administration & dosage ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; pathology ; Cisplatin ; administration & dosage ; DNA-Binding Proteins ; genetics ; Exons ; Female ; Genotype ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; pathology ; Male ; Middle Aged ; Neoplasm Staging ; Nuclear Proteins ; genetics ; Paclitaxel ; administration & dosage ; Polymorphism, Genetic ; Tumor Protein p73 ; Tumor Suppressor Protein p53 ; genetics ; Tumor Suppressor Proteins ; genetics

OBJECTIVETo study the relationship between two potential functional polymorphisms in exon 2 of the p73 gene and the susceptibility of lung cancer.

METHODSGenotypes were determined by polymerase chain reaction-single stand conformation polymorphism (PCR-SSCP) method in 425 histologically-confirmed lung cancer cases and 588 cancer-free controls, frequency-matched by age and sex.

RESULTSThe two polymorphisms were in complete linkage disequilibrium and the frequencies of variant p73 AT haplotype (A4T14) were less commonly seen in the cases (0.225) than in the controls (0.287) (P = 0.0018). Compared with the p73 GC/GC homozygotes, both the AT/AT variant homozygotes and GC/AT heterozygotes were associated with a significantly decreased risk [adjusted odds ratio (OR) = 0.45, 95% confidence interval (CI) = 0.26 - 0.80 and OR = 0.70, 95% CI = 0.53-0.92, respectively].

CONCLUSIONThese results suggested that this p73 dinucleotide polymorphism might have had a role to play in the susceptibility of lung cancer.

5' Untranslated Regions ; genetics ; Adenocarcinoma ; genetics ; Adult ; Aged ; Carcinoma, Small Cell ; genetics ; DNA-Binding Proteins ; genetics ; Exons ; genetics ; Female ; Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor ; physiology ; Genetic Predisposition to Disease ; genetics ; Humans ; Lung Neoplasms ; genetics ; Male ; Middle Aged ; Nuclear Proteins ; genetics ; Polymorphism, Genetic ; Tumor Protein p73 ; Tumor Suppressor Proteins ; genetics