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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Koutb F, Abdel-Rahman S, Hassona E, Haggag A. Association of C-myc and p53 Gene Expression and Polymorphisms with Hepatitis C (HCV) Chronic Infection, Cirrhosis and Hepatocellular Carcinoma (HCC) Stages in
Egypt. Asian Pac J Cancer Prev 2017; 18:2049-2057. [PMID: 28843220 PMCID: PMC5697458 DOI: 10.22034/apjcp.2017.18.8.2049] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The aim of this study is to investigate c-myc and p53 gene expression and polymorphisms in different stages of HCV infection,. Expression levels of c-myc and p53 were evaluated by RT-PCR and polymorphisms were determined by PCR-RFLP in 60 HCV patients classified into chronic infection, cirrhosis and HCC groups along with 30 controls. c-myc gene expression significant increased through the stages as compared to the control level (1.17, 1.82, 3.33 and 0.32, respectively), whereas p53 significantly declined (4,375, 3,842, 525 and 5,498, respectively). The C-myc CC genotype was predominant in the HCC group (90%) to a greater extent than in the cirrhosis, chronic infection and control cases (80%, 20% and 10%, respectively), while the GG genotype was predominant in controls (83%, as compared to 65%, 10% and 10%). The CG genotype was most common in chronic infection (15%). The p53 PP genotype predominated in controls (87%, with 15%, 10% and 20%, respectively, for the three stages) while the AA genotype demonstrated only slight increase to HCC (13%, 25% and 30%, respectively) and PA genotype was predominant in cirrhosis cases (90%). These findings reveal that c-myc and p53 gene expression and polymorphisms may be considered as promising sensitive genetic biomarkers for progression of HCV infection.
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Affiliation(s)
- Fayed Koutb
- Department of Nucleic Acid Research, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications, Egypt.
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Abd-Rabou AA, Eskander EF, Mohamed MS, Yahya SM, Sherbini AE, Shaker OG. P53 rs1042522 and CD95 rs1800682 genetic variations in HCV-4a response to antiviral therapy. Genes Dis 2015; 2:197-210. [PMID: 30258864 PMCID: PMC6150111 DOI: 10.1016/j.gendis.2015.02.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 02/05/2015] [Indexed: 12/17/2022] Open
Abstract
Current estimates indicate that the hepatitis C (HCV) is the leading cause of mortality around the world, with infection rates steadily increasing in Egypt. The dual therapy for this silent epidemic with pegylated-interferon-α2b/ribavirin has markedly improved the success rates in genotype-4 patients. It was reported that apoptosis plays a vital mechanistic role in limiting viral replication. P53, a key regulator of apoptosis, induces CD95 gene expression and subsequently initiates apoptotic cascade to be activated. The current study examined the impact of P53 rs1042522 and CD95 rs1800682 polymorphisms on the treatment response. Three groups of 240 volunteers were enrolled in this study; 86 in sustained virological responders group, 74 in non-responders group, and 80 in control group. All patients had HCV genotype-4a and were interferon treatment naïve. Quantizations of HCV-RNA by qRT-PCR and histological scores were performed for all patients. In addition, genotyping of HCV-RNA, P53 rs1042522 Arg/Pro and CD95 rs1800682 A/G polymorphisms were investigated in all subjects. It was resulted that P53 Pro/Pro homozygous genotype has high significant increase, while CD95 A/A homozygous genotype has high significant decrease when comparing non-responders with responders. Finally, it was concluded that Pro variant of P53 rs1042522 may be used as a genetic predictor for non-responsiveness, while A/A variant of CD95 rs1800682 may be used as a sensitive biomarker for responsiveness to antiviral therapy of HCV genotype-4a infection. In addition, low prolactin, high total testosterone, and high GH levels may provide promising biomarkers for early prediction of the response when associated with these genetic polymorphisms.
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Affiliation(s)
- Ahmed A. Abd-Rabou
- Hormones Department, Medical Research Division, National Research Centre, Cairo 12622, Egypt
| | - Emad F. Eskander
- Hormones Department, Medical Research Division, National Research Centre, Cairo 12622, Egypt
| | - Mervat S. Mohamed
- Chemistry Department, Biochemistry Specialty, Faculty of Science, Cairo University, Egypt
| | - Shaymaa M.M. Yahya
- Hormones Department, Medical Research Division, National Research Centre, Cairo 12622, Egypt
| | - Ashraf El Sherbini
- Internal Medicine Department, Medical Research Division, National Research Centre, Cairo, Egypt
| | - Olfat G. Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Egypt
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Eskander EF, Abd-Rabou AA, Mohamed MS, Yahya SMM, El Sherbini A, Shaker OG. The potential impact of P53 and APO-1 genetic polymorphisms on hepatitis C genotype 4a susceptibility. Gene 2014; 550:40-5. [PMID: 25108128 DOI: 10.1016/j.gene.2014.08.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Revised: 08/01/2014] [Accepted: 08/05/2014] [Indexed: 01/06/2023]
Abstract
The hepatitis C virus (HCV), the main cause of morbidity and mortality, is endemic worldwide. HCV causes cirrhosis and other complications that often lead to death. HCV is most common in underdeveloped nations, with the highest prevalence rates in Egypt. Tumor suppressor gene (P53) induces the expression of apoptotic antigen-1 gene (APO-1) by binding to its promoter for mediating apoptosis; an important mechanism for limiting viral replication. This study aims at investigating the impact of P53 72 Arg/Pro and APO-1 -670 A/G polymorphisms on HCV genotype 4a susceptibility. Two hundred and forty volunteers were enrolled in this study and divided into two major groups; 160 HCV infected patient group and 80 healthy control group. HCV patients were classified according to Metavir scoring system into two subgroups; 72 patients in F0/1-HCV subgroup (patients with no or mild fibrotic stages) and 38 patients in F3/4-HCV subgroup (patients with advanced fibrotic stages). Quantification of HCV-RNA by qRT-PCR and fibrotic scores as well as genotyping of HCV-RNA, P53 at 72 Arg/Pro, and APO-1 at -670 A/G were performed for all subjects. It was resulted that F0/1-HCV patients have significant differences of P53 at 72 (Pro/Pro and Arg/Arg) genotypes and dominant/recessive genetic models as well as APO-1 -670 A/A genotype and dominant genetic model as compared to F3/4-HCV patients. Moreover, HCV patients have significant differences of P53 at 72 (Pro/Pro) genotype and recessive genetic model as well as APO-1 -670 A/A genotype and dominant genetic model as compared to those of healthy individuals. Finally, it was concluded that P53 rs 1042522 (Pro/Pro and Arg/Arg) genotypes and APO-1 rs 1800682 A/A genotype may be potentially used as sensitive genetic markers for HCV genotype 4a susceptibility.
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Affiliation(s)
- Emad F Eskander
- Hormones Department, Medical Research Division, National Research Centre, Cairo, Egypt
| | - Ahmed A Abd-Rabou
- Hormones Department, Medical Research Division, National Research Centre, Cairo, Egypt.
| | - Mervat S Mohamed
- Chemistry Department, Biochemistry Specialty, Faculty of Science, Cairo University, Egypt
| | - Shaymaa M M Yahya
- Hormones Department, Medical Research Division, National Research Centre, Cairo, Egypt
| | - Ashraf El Sherbini
- Internal Medicine Department, Medical Research Division, National Research Centre, Cairo, Egypt
| | - Olfat G Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Egypt
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"P53 codon 72 single base substitution in viral hepatitis C and hepatocarcinoma incidences". Indian J Clin Biochem 2014; 29:3-7. [PMID: 24478542 DOI: 10.1007/s12291-013-0317-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Accepted: 03/19/2013] [Indexed: 01/16/2023]
Abstract
Viral infection with hepatitis C virus (HCV) has a high propensity in becoming chronic and it is the major cause of hepatocellular carcinoma (HCC) worldwide. This review was basically established to illustrate the putative role of the P53 gene Arg72Pro polymorphism on various cancer models and viral infections, focusing on HCV and HCC incidences. Authors studied the 72 G/C single base substitution of P53 gene at codon 72 using various polymorphic techniques. Intriguingly, authors investigated that the P53 codon 72 plays a crucial role as risk factor in several cancer models. Others found that there is no association between codon 72 genotypes and HCV disease severity or liver cancer. Moreover, the lack of a significant relationship between this polymorphism and risk of HCC shows that it does not predispose towards hepatocarcinogenesis and the frequent loss of the proline allele in HCV-associated carcinogenesis of the liver plays some critical role in hepatocarcinogenesis. Amazingly, there is a significant correlation between male homozygotes for P53 72Pro with HCV type 1b infection. However, there was no significant difference between the P53 polymorphism and HCV genotypes 2a and 2b. It was concluded that the P53 gene polymorphism at codon 72 has been investigated as potential risk factor in several cancer models and HCV infections.
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Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant neoplasms worldwide. The p53 gene is frequently mutated in some histological subtypes of HCC. The role of p53 mutations and polymorphic variant of codon 72 in the prognosis of disease is still unclear. The p53 tumor suppressor gene Arg72Pro polymorphism has been associated with HCC. However, results were inconsistent. This meta-analysis was performed to estimate the association between p53 Arg72Pro polymorphism and HCC or HCC infected by HBV/HCV. METHODS Electronic search of PubMed was conducted to select studies. Studies containing available genotype frequencies of Arg72Pro were chosen, and pooled odds ratio (OR) with 95 % confidence interval (CI) was used to assess the association. RESULTS Ten published studies, including 1,371 HCC cases and 2,517 controls were identified. The overall results suggested that the variant genotypes were associated with the HCC risk (Pro/Pro vs. Pro/Arg + Arg/Arg: OR 1.355, 95 % CI 1.041-1.764, p = 0.024). In the stratified analysis, individuals with the Pro/Pro in the recessive model had increased risk of HCC (OR 1.927, 95 % CI 1.127-3.297, p = 0.017) in Caucasian. A symmetric funnel plot, the Begg's test, was suggestive of the lack of publication bias. There was no association between the p53 codon 72 polymorphism and HBV/HCV-positive HCC. CONCLUSION This meta-analysis suggests that p53 condon 72 Pro/Progenotypes are associated with increased risk of HCC in Caucasian. To validate this association, further studies with larger participants worldwide are needed to examine the associations between this polymorphism and HCC.
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Abstract
In addition to viral and environmental/behavioural factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes in hepatitis C virus (HCV) infection. This paper reviews the literature with respect to studies of host genetic determinants of HCV outcome and attempts to highlight trends and synthesise findings. With respect to the susceptibility to HCV infection, several studies have replicated associations of the HLA class II alleles DQB1(*)0301 and DRB1(*)11 with self-limiting infection predominantly in Caucasian populations. Meta-analyses yielded summary estimates of 3.0 (95% CI: 1.8-4.8) and 2.5 (95% CI: 1.7-3.7) for the effects of DQB1(*)0301 and DRB1(*)11 on self-limiting HCV, respectively. Studies of genetics and the response to interferon-based therapies have largely concerned single-nucleotide polymorphisms and have been inconsistent. Regarding studies of genetics and the progression of HCV-related disease, there is a trend with DRB1(*)11 alleles and less severe disease. Studies of extrahepatic manifestations of chronic HCV have shown an association between DQB1(*)11 and DR3 with the formation of cryoglobulins. Some important initial observations have been made with respect to genetic determinants of HCV outcome. Replication studies are needed for many of these associations, as well as biological data on the function of many of these polymorphisms.
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Affiliation(s)
- L J Yee
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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He QQ, Cheng RX, Sun Y, Feng DY, Chen ZC, Zheng H. Hepatocyte transformation and tumor development induced by hepatitis C virus NS3 C-terminal deleted protein. World J Gastroenterol 2003; 9:474-8. [PMID: 12632500 PMCID: PMC4621564 DOI: 10.3748/wjg.v9.i3.474] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect of hepatitis C virus nonstructural protein 3 c-terminal deleted protein (HCV NS3-5’) on hepatocyte transformation and tumor development.
METHODS: QSG7701 cells were transfected with plasmid pRcHCNS3-5’ (expressing HCV NS3 c-terminal deleted protein) by lipofectamine and selected in G418. The expression of HCV NS3 gene and protein was determined by PCR and immunohistochemistry respectively. Biological behavior of transfected cells was observed through cell proliferation assay, anchorage-independent growth and tumor development in nude mice. The expression of HCV NS3 and c-myc proteins in the induced tumor was evaluated by immunohistochemistry.
RESULTS: HCV NS3 was strongly expressed in QSG7701 cells transfected with plasmid pRcHCNS3-5’ and the positive signal was located in cytoplasm. Cell proliferation assay showed that the population doubling time in pRcHCNS3-5’ transfected cells was much shorter than that in pRcCMV and non-transfected cells (24 h, 26 h, 28 h respectively). The cloning ratio of cells transfected with pRcHCNS3-5’, pRcCMV and non-transfected cells was 33%, 1.46%, 1.11%, respectively, the former one was higher than that in the rest two groups (P < 0.01). Tumor development was seen in nude mice inoculated with pRcHCNS3-5’ transfected cells after 15 days. HE staining showed its feature of hepatocarcinoma, and immunohistochemistry confirmed the expressions of HCV NS3 and c-myc proteins in tumor tissue. The positive control group inoculated with HepG2 also showed tumor development, while no tumor developed in the nude mice injected with pRcCMV and non-transfected cells after 40 days.
CONCLUSION: 1.HCV NS3 c-terminal deleted protein has transforming and oncogenic potential. 2. Human liver cell line QSG7701 may be used as a good model to study HCV NS3 pathogenesis.
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Affiliation(s)
- Qiong-Qiong He
- Department of Pathology, Xiangya School of Medicine, Central South University, Changsha 410078, Hunan Province, China
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Baccouche S, Mabrouk I, Said S, Mosbah A, Jlidi R, Gargouri A. A more accurate detection of codon 72 polymorphism and LOH of the TP53 gene. Cancer Lett 2003; 189:91-6. [PMID: 12445682 DOI: 10.1016/s0304-3835(02)00405-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The polymorphism at codon 72 of the TP53 gene has been extensively studied for its involvement in cancerogenesis and loss of heterozygosity (LOH) detection. Usually, the exon 4 of the TP53 gene is amplified by polymerase chain reaction (PCR) on DNA extracted from blood and tumor tissues, then digested by AccII. In the case of heterozygosity, the comparison of AccII profile from blood and tumor DNA PCR products allowed the identification of a potential LOH in the TP53 locus. This method can be hindered by a partial AccII digestion and/or DNA contamination of non-tumor cells. To circumvent these problems, we have developed a new approach by using the AccII restriction site between exon 4 and exon 6. The PCR amplification of exon 4-6, followed by AccII digestion allowed us to detect without ambiguity any LOH case.
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Affiliation(s)
- Sami Baccouche
- Laboratory Génétique Moléculaire des Eucaryotes, Centre de Biotechnologie de Sfax, BP'K' 3038, Sfax, Tunisia
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