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Romualdo GR, Leroy K, Costa CJS, Prata GB, Vanderborght B, da Silva TC, Barbisan LF, Andraus W, Devisscher L, Câmara NOS, Vinken M, Cogliati B. In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling. Cancers (Basel) 2021; 13:5583. [PMID: 34771745 PMCID: PMC8582701 DOI: 10.3390/cancers13215583] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/02/2021] [Accepted: 11/04/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.
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Affiliation(s)
- Guilherme Ribeiro Romualdo
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo (USP), São Paulo 05508-270, Brazil; (G.R.R.); (C.J.S.C.); (T.C.d.S.)
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu 18618-689, Brazil; (G.B.P.); (L.F.B.)
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | - Kaat Leroy
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (K.L.); (M.V.)
| | - Cícero Júlio Silva Costa
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo (USP), São Paulo 05508-270, Brazil; (G.R.R.); (C.J.S.C.); (T.C.d.S.)
| | - Gabriel Bacil Prata
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu 18618-689, Brazil; (G.B.P.); (L.F.B.)
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, Brazil
| | - Bart Vanderborght
- Gut-Liver Immunopharmacology Unit, Basic and Applied Medical Sciences, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium;
- Hepatology Research Unit, Internal Medicine and Paediatrics, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium;
| | - Tereza Cristina da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo (USP), São Paulo 05508-270, Brazil; (G.R.R.); (C.J.S.C.); (T.C.d.S.)
| | - Luís Fernando Barbisan
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu 18618-689, Brazil; (G.B.P.); (L.F.B.)
| | - Wellington Andraus
- Department of Gastroenterology, Clinics Hospital, School of Medicine, University of São Paulo (HC-FMUSP), São Paulo 05403-000, Brazil;
| | - Lindsey Devisscher
- Hepatology Research Unit, Internal Medicine and Paediatrics, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium;
| | - Niels Olsen Saraiva Câmara
- Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo 05508-000, Brazil;
| | - Mathieu Vinken
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (K.L.); (M.V.)
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo (USP), São Paulo 05508-270, Brazil; (G.R.R.); (C.J.S.C.); (T.C.d.S.)
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Yasin HK, Taylor AH, Ayakannu T. A Narrative Review of the Role of Diet and Lifestyle Factors in the Development and Prevention of Endometrial Cancer. Cancers (Basel) 2021; 13:cancers13092149. [PMID: 33946913 PMCID: PMC8125712 DOI: 10.3390/cancers13092149] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/12/2021] [Accepted: 04/16/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary The incidence and prevalence of endometrial cancer is increasing globally. The main factors involved in this increase have been the way women live today and what they eat and drink. In fact, the obesity pandemic that is sweeping across the planet is considered to be the main contributory feature. This review aims to introduce to a new audience, those that are not experts in the field, what is known about the different types of endometrial cancer and the mechanisms for their induction and protection. We also seek to summarise the existing knowledge on dietary and lifestyle factors that prevent endometrial development in susceptible populations and identify the main problem in this arena; the paucity of research studies and clinical trials that investigate the interaction(s) between diet, lifestyle and endometrial cancer risk whilst highlighting those areas of promise that should be further investigated. Abstract Endometrial cancer is the most common cancer affecting the reproductive organs of women living in higher-income countries. Apart from hormonal influences and genetic predisposition, obesity and metabolic syndrome are increasingly recognised as major factors in endometrial cancer risk, due to changes in lifestyle and diet, whereby high glycaemic index and lipid deposition are prevalent. This is especially true in countries where micronutrients, such as vitamins and minerals are exchanged for high calorific diets and a sedentary lifestyle. In this review, we will survey the currently known lifestyle factors, dietary requirements and hormonal changes that increase an individual’s risk for endometrial cancer and discuss their relevance for clinical management. We also examine the evidence that everyday factors and clinical interventions have on reducing that risk, such that informed healthy choices can be made. In this narrative review, we thus summarise the dietary and lifestyle factors that promote and prevent the incidence of endometrial cancer.
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Affiliation(s)
- Hajar Ku Yasin
- Department of Obstetrics & Gynaecology, Cumberland Infirmary, Carlisle CA2 7HY, UK;
| | - Anthony H. Taylor
- Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK;
| | - Thangesweran Ayakannu
- Gynaecology Oncology Cancer Centre, Liverpool Women’s NHS Foundation Trust, Liverpool Women’s Hospital, Liverpool L8 7SS, UK
- Correspondence: ; Tel.: +44-(0)-151-708-9988 (ext. 4531)
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Regulation of expression of drug-metabolizing enzymes by oncogenic signaling pathways in liver tumors: a review. Acta Pharm Sin B 2020; 10:113-122. [PMID: 31993310 PMCID: PMC6976994 DOI: 10.1016/j.apsb.2019.06.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/23/2019] [Accepted: 06/24/2019] [Indexed: 02/06/2023] Open
Abstract
Mutations in genes encoding key players in oncogenic signaling pathways trigger specific downstream gene expression profiles in the respective tumor cell populations. While regulation of genes related to cell growth, survival, and death has been extensively studied, much less is known on the regulation of drug-metabolizing enzymes (DMEs) by oncogenic signaling. Here, a comprehensive review of the available literature is presented summarizing the impact of the most relevant genetic alterations in human and rodent liver tumors on the expression of DMEs with a focus on phases I and II of xenobiotic metabolism. Comparably few data are available with respect to DME regulation by p53-dependent signaling, telomerase expression or altered chromatin remodeling. By contrast, DME regulation by constitutive activation of oncogenic signaling via the RAS/RAF/mitogen-activated protein kinase (MAPK) cascade or via the canonical WNT/β-catenin signaling pathway has been analyzed in greater depth, demonstrating mostly positive-regulatory effects of WNT/β-catenin signaling and negative-regulatory effects of MAPK signaling. Mechanistic studies have revealed molecular interactions between oncogenic signaling and nuclear xeno-sensing receptors which underlie the observed alterations in DME expression in liver tumors. Observations of altered DME expression and inducibility in liver tumors with a specific gene expression profile may impact pharmacological treatment options.
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Yu C, Zhou Z, Wang J, Sun J, Liu W, Sun Y, Kong B, Yang H, Yang S. In depth analysis of apoptosis induced by silica coated manganese oxide nanoparticles in vitro. JOURNAL OF HAZARDOUS MATERIALS 2014; 283:519-528. [PMID: 25464291 DOI: 10.1016/j.jhazmat.2014.09.060] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Revised: 06/10/2014] [Accepted: 09/22/2014] [Indexed: 06/04/2023]
Abstract
Manganese oxide nanoparticles (MnO NPs) have been regarded as a new class of T1-positive contrast agents. The cytotoxicity of silica coated MnO NPs (MnO@SiO2 NPs) was investigated in human cervical carcinoma cells (HeLa) and mouse fibroblast cells (L929). The changes of cell viability, cell morphology, cellular oxidative stress, mitochondrial membrane potential and cell cycle induced by MnO@SiO2 NPs were evaluated. Compared to HeLa cells, L929 cells showed lower cell viability, more strongly response to oxidative stress and higher percentage in the G2/M phase of cell cycle. The appearance of sub-G1 peak, double staining with Annexin V-FITC/PI and the increase of Caspase-3 activity further confirmed apoptosis should be the major form of cell death. Moreover, the apoptotic pathway was clarified as follows. Firstly, reactive oxygen species (ROS) is generated induced by MnO@SiO2 NPs, then p53 is activated followed by an increase in the bax and a decrease in the bcl-2, ultimately leading to G2/M phase arrest, increasing the activity of caspase-3 and inducing apoptosis.
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Affiliation(s)
- Chao Yu
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China
| | - Zhiguo Zhou
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China.
| | - Jun Wang
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China
| | - Jin Sun
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China
| | - Wei Liu
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China
| | - Yanan Sun
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China
| | - Bin Kong
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China
| | - Hong Yang
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China
| | - Shiping Yang
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China; The Education Ministry Key Lab of Pesticide & Chemical Biology, South China Agricultural University, Guangzhou 510641, China.
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Cruz A, Madruga C, Mallmann C, Moreira E, Botura M, Silva G, Batatinha M. Investigação do gene p53 de frangos expostos às aflatoxinas. ARQ BRAS MED VET ZOO 2012. [DOI: 10.1590/s0102-09352012000600036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Identificou-se o efeito das aflatoxinas (AFs) sobre o gene p53 de frangos de corte, de linhagem comercial, separados em: grupo experimental, tratado (GT) com ração comercial contendo 2,8ppm de AFs totais durante 21 dias consecutivos, e grupo-controle (GC), sem exposição às AFs. Macroscopicamente, as alterações caracterizaram-se por hepatomegalia e aspecto pálido-amarelado com alguns focos hemorrágicos e, histologicamente, por desarranjo trabecular, pleomorfismo hepatocítico com cariomegalia, degeneração vacuolar intracitoplasmática, necrose com infiltração linfocítica e hiperplasia de ductos biliares. A PCR com os primers GSPT53c-1 com base no gene candidato a p53 (GenBank XM_424937.2) gerou um produto de aproximadamente 350 pares de base. O amplicon sequenciado a partir do DNA dos frangos do GT não apresentou mutação ou deleção, assim como padrão de bandas do PCR-RFLP não foi distinto entre ambos os grupos experimentais e a sequência depositada no banco de genes. Os resultados sugerem que não ocorreu transversão devido à exposição às AFs no fragmento amplificado. Conclui-se que a PCR-RFLP e o sequenciamento do produto da PCR não são ferramentas apropriadas para diagnóstico da exposição de frangos às AFs nas condições experimentais empregadas.
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Yang TP, Lee HJ, Ou TT, Chang YJ, Wang CJ. Mulberry leaf polyphenol extract induced apoptosis involving regulation of adenosine monophosphate-activated protein kinase/fatty acid synthase in a p53-negative hepatocellular carcinoma cell. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2012; 60:6891-6898. [PMID: 22676643 DOI: 10.1021/jf302183x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
The polyphenols in mulberry leaf possess the ability to inhibit cell proliferation, invasion, and metastasis of tumors. It was reported that the p53 status plays an important role in switching apoptosis and the cell cycle following adenosine monophosphate-activated protein kinase (AMPK) activation. In this study, we aimed to detect the effect of the mulberry leaf polyphenol extract (MLPE) on inducing cell death in p53-negative (Hep3B) and p53-positive (Hep3B with transfected p53) hepatocellular carcinoma cells and also to clarify the role of p53 in MLPE-treated cells. After treatment of the Hep3B cells with MLPE, apoptosis was induced via the AMPK/PI3K/Akt and Bcl-2 family pathways. Transient transfection of p53 into Hep3B cells led to switching autophagy instead of apoptosis by MLPE treatment. We demonstrated that acridine orange staining and protein expressions of LC-3 and beclin-1 were increased in p53-transfected cells. These results implied induction of apoptosis or autophagy in MLPE-treated hepatocellular carcinoma cells can be due to the p53 status. We also found MLPE can not only activate AMPK but also diminish fatty acid synthase, a molecular target for cancer inhibition. At present, our results indicate MLPE can play an active role in mediating the cell death of hepatocellular carcinoma cells and the p53 might play an important role in regulating the death mechanisms.
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Affiliation(s)
- Tzi-Peng Yang
- School of Medical Laboratory and Biotechnology and ‡Institute of Biochemistry and Biotechnology, Chung-Shan Medical University , Taichung, Taiwan
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Baldwin T, Riley R, Zitomer N, Voss K, Coulombe Jr. R, Pestka J, Williams D, Glenn A. The current state of mycotoxin biomarker development in humans and animals and the potential for application to plant systems. WORLD MYCOTOXIN J 2011. [DOI: 10.3920/wmj2011.1292] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Filamentous fungi that contaminate livestock feeds and human food supply often produce toxigenic secondary metabolites known as mycotoxins. Among the hundreds of known mycotoxins, aflatoxins, deoxynivalenol, fumonisins, ochratoxin A and zearalenone are considered the most commercially important. Intense research on these mycotoxins, especially aflatoxin, has resulted in the development of 'biomarkers' used to link exposure to disease risk. In the case of aflatoxin this effort has led to the discovery of both exposure and mechanism-based biomarkers, which have proven essential for understanding aflatoxin's potential for causing disease in humans, including subtle effects on growth and immune response. Fumonisin biomarkers have also been used extensively in farm and laboratory animals to study the fumonisin-induced disruption of cellular and systemic physiology which leads to disease. This review summarises the status of mycotoxin biomarker development in humans and animals for the commercially important mycotoxins. Since the fungi responsible for the production of these mycotoxins are often endophytes that infect and colonise living plant tissues, accumulation of mycotoxins in the plant tissues may at times be associated with development of plant disease symptoms. The presence of mycotoxins, even in the absence of disease symptoms, may still have subtle biological effects on the physiology of plants. This review examines the question of whether or not the knowledge gained from mechanistic studies and development of biomarkers in animal and human systems is transferable to the study of mycotoxin effects on plant systems. Thus far, fumonisin has proven amenable to development of mechanism-based biomarkers to study maize seedling disease caused by the fumonisin producer, Fusarium verticillioides. Expanding our knowledge of mechanisms of toxicity and the overt and subtle effects on animal, human, and plant systems through the identification and validation of biomarkers will further our ability to monitor and limit the damage and economic impact of mycotoxins.
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Affiliation(s)
- T. Baldwin
- Toxicology and Mycotoxin Research Unit, USDA, ARS, 950 College Station Road, Athens GA 30605, USA
- Department of Plant Pathology, University of Georgia, 2105 Miller Plant Science Building, Athens GA 30602-7274, USA
| | - R. Riley
- Toxicology and Mycotoxin Research Unit, USDA, ARS, 950 College Station Road, Athens GA 30605, USA
| | - N. Zitomer
- Toxicology and Mycotoxin Research Unit, USDA, ARS, 950 College Station Road, Athens GA 30605, USA
| | - K. Voss
- Toxicology and Mycotoxin Research Unit, USDA, ARS, 950 College Station Road, Athens GA 30605, USA
| | - R. Coulombe Jr.
- Department of Veterinary Sciences, Utah State University, 4815 Old Main Hill, Logan UT 84322-4620, USA
| | - J. Pestka
- Department of Food Science and Human Nutrition, Michigan State University, 234 GM Trout Building, East Lansing MI 48824-1224, USA
| | - D. Williams
- Department of Environmental and Molecular Toxicology, Oregon State University, 1007 Agriculture & Life Sciences Building, Corvallis, OR 97331, USA
| | - A. Glenn
- Toxicology and Mycotoxin Research Unit, USDA, ARS, 950 College Station Road, Athens GA 30605, USA
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Wild CP, Montesano R. A model of interaction: aflatoxins and hepatitis viruses in liver cancer aetiology and prevention. Cancer Lett 2009; 286:22-8. [PMID: 19345001 DOI: 10.1016/j.canlet.2009.02.053] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2008] [Accepted: 02/27/2009] [Indexed: 12/21/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has an extremely poor prognosis. The majority of cases occur in south-east Asia and sub-Saharan Africa where the major risk factors are chronic infection with hepatitis B and C viruses (HBV and HCV) as well as dietary exposure to aflatoxins. Aflatoxin B1, the most commonly occurring and potent of the aflatoxins is associated with a specific AGG to AGT transversion mutation at codon 249 of the p53 gene in human HCC, providing mechanistic support to a causal link between exposure and disease. Prospective epidemiological studies have shown a more than multiplicative interaction between HBV and aflatoxins in terms of HCC risk. However, the biology underlying this statistical interaction is not fully understood. There are a number of potential mechanisms including, among others: the fixation of AFB1-induced mutations in the presence of liver regeneration and hyperplasia induced by chronic HBV infection; the predisposition of HBV-infected hepatocytes to aflatoxin-induced DNA damage; an increase in susceptibility to chronic HBV infection in aflatoxin-exposed individuals; and oxidative stress exacerbated by co-exposure to aflatoxins and chronic hepatitis infection. Priorities for prevention are global HBV vaccination, primary and secondary prevention strategies against aflatoxin and the avoidance of transmission of HCV through good hygiene practices.
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Affiliation(s)
- Christopher P Wild
- Molecular Epidemiology Unit, Centre for Epidemiology and Biostatistics, Light Laboratories, University of Leeds, Leeds, UK.
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Abstract
BACKGROUND/AIMS Mutations of p53 gene have been detected in precancerous stages of several cancers, and the possible role in multistep carcinogenesis is suggested. The aim of this study was to examine the mutation profile of p53 gene in regenerative nodules in cirrhotic livers. METHODS Ninety eight tissue specimens of regenerative nodules obtained from 15 cases of cirrhosis were used for analysis. Twenty cases of chronic hepatitis and two cases of fatty liver were used as controls. DNA was extracted from each of manually demarcated regenerative nodules, and nucleotide sequence analysis was performed on p53 gene exon 5. RESULTS Direct sequencing detected p53 mutations in seven of 98 DNA samples (7.1%) from regenerative nodules in six cases of cirrhosis. Subcloning analysis revealed that mutation sites differed in each subclone and the incidences of the mutation varied from 7.7 to 58.8% depending on individual nodules. The mutation was not detected in any of chronic hepatitis and fatty liver. There were inconsistent p53 sequence with regenerative nodules and accompanied hepatocellular carcinomas in six cases. CONCLUSIONS Mutations of p53 gene were frequently found in cirrhotic livers compared with livers of patients with chronic hepatitis (P<0.01), suggesting that p53 mutations at the stage of cirrhosis may be a causative factor that may potentially lead to hepatocellular carcinoma.
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Affiliation(s)
- Keiji Minouchi
- Gastroenterology, Kanazawa University Hospital, Cancer Gene Regulation, Kanazawa University Graduate School of Medicine, Takara-machi 13-1, Ishikawa 920-8641, Japan
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Liu H, Wang Y, Zhou Q, Gui SY, Li X. The point mutation of p53 gene exon7 in hepatocellular carcinoma from Anhui Province, a non HCC prevalent area in China. World J Gastroenterol 2002; 8:480-2. [PMID: 12046074 PMCID: PMC4656425 DOI: 10.3748/wjg.v8.i3.480] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [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: In hepatocellular carcinoma (HCC) prevalent areas of China, the point mutation of p53 exon7 is highly correlated with Hepatitis B virus (HBV) infection and aflatoxin B intake. While in non-HCC-prevalent areas of China, these factors are not so important in the etiology of HCC. Therefore, the point mutation of p53 exon7 may also be different than that in HCC-prevalent areas of China. The aim of this study is to investigate the status and carcinogenic role of the point mutation of p53 gene exon7 in hepatocellular carcinoma from Anhui Province, a non-HCC-prevalent area in China.
METHODS: PCR, PCR-SSCP and PCR-RFLP were applied to analyze the homozygous deletion and point mutation of p53 exon7 in HCC samples from Anhui, which were confirmed by DNA sequencing and Genbank comparison.
RESULTS: In the 38 samples of hepatocellular carcinoma, no homozygous deletion of p53 exon7 was detected and point mutations of p53 exon7 were found in 4 cases, which were found to be heterozygous mutation of codon 249 with a mutation rate of 10.53% (4/38). The third base mutation (GiúT) of p53 codon 249 was found by DNA sequencing and Genbank comparison.
CONCLUSION: The incidence of point mutation of p53 codon 249 is lower in hepatocellular carcinoma and the heterozygous mutation of p53 exon7 found in these patients only indicate that they have genetic susceptibility to HCC. p53 codon 249 is a hotspot of p53 exon7 point mutation, suggesting that the point mutation of p53 exon 7 may not play a major role in the carcinogenesis of HCC in Anhui Province, a non-HCC-prevalent area in China.
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Affiliation(s)
- Hu Liu
- Laboratory of Molecular Biology and Department of biochemistry, Anhui Medical University, Hefei 230032, Anhui Province, China
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Smela ME, Currier SS, Bailey EA, Essigmann JM. The chemistry and biology of aflatoxin B(1): from mutational spectrometry to carcinogenesis. Carcinogenesis 2001; 22:535-45. [PMID: 11285186 DOI: 10.1093/carcin/22.4.535] [Citation(s) in RCA: 186] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Dietary exposure to aflatoxin B(1) (AFB(1)) is associated with an increased incidence of hepatocellular carcinoma (HCC), especially in populations in which exposure to hepatitis B virus (HBV) is a common occurrence. Most HCC samples from people living where HBV is prevalent have one striking mutational hotspot: a GC-->TA transversion at the third position of codon 249 of the p53 gene. In this review, the chemical reaction of an electrophilic derivative of aflatoxin with specific DNA sequences is examined, along with the types of mutations caused by AFB(1) and the sequence context dependence of those mutations. An attempt is made to assign the source of these mutations to specific chemical forms of AFB(1)-DNA damage. In addition, epidemiological and experimental data are examined regarding the synergistic effects of AFB(1) and HBV on HCC formation and the predominance of one hotspot GC-->TA transversion in the p53 gene of affected individuals.
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Affiliation(s)
- M E Smela
- Department of Chemistry and Division of Bioengineering and Environmental Health Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Cachot J, Cherel Y, Galgani F, Vincent F. Evidence of p53 mutation in an early stage of liver cancer in European flounder, Platichthys flesus (L.). Mutat Res 2000; 464:279-87. [PMID: 10648915 DOI: 10.1016/s1383-5718(99)00205-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
A number of flounders dwelling in highly contaminated coastal areas of Northern Europe develop liver tumours. In order to increase our understanding of the molecular pathogenesis of these sporadic tumours, we examined p53 mutations in eleven hyperplasia and six adenoma. p53 introns 4 to 8 were first sequenced to allow individual amplification of exons 5 to 8. DNA extracted from formalin-fixed livers was amplified and PCR products were directly sequenced. Two major results were obtained. (i) Flounders from different geographical areas displayed a high rate of sequence variation. Base substitutions were identified in both tumour and normal tissues and thus may be considered as polymorphic variations in individuals. (ii) One mutation was detected in two hyperplastic foci from the same flounder. This mutation was a T:A to A:T transversion at codon 147, resulting in the replacement of valine for glutamic acid. This residue took place in the L2 loop of the DNA binding surface. Its substitution by an hydrophilic and charged residue could thus impair p53 (protein) biological activity.
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Affiliation(s)
- J Cachot
- IFREMER, Dép. Polluants Chimiques, B.P. 21105, 44311, Nantes, France.
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Garcia SB, Park HS, Novelli M, Wright NA. Field cancerization, clonality, and epithelial stem cells: the spread of mutated clones in epithelial sheets. J Pathol 1999; 187:61-81. [PMID: 10341707 DOI: 10.1002/(sici)1096-9896(199901)187:1<61::aid-path247>3.0.co;2-i] [Citation(s) in RCA: 102] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
There has been considerable debate about the origin of human tumours, whether they arise from a single cell and are clonal populations or whether there needs to be some sort of co-operativity between cells for the neoplastic process to begin. Current theories subscribe to the clonal view, where a series of mutations in one cell begins a process of selection and clonal evolution leading to the development of the malignant phenotype. This review approaches this problem by asking how mutated clones, once established, spread through tissues before becoming overtly invasive. While there is substantial evidence in favour of independent origins of each tumour from a unique mutated clone, there are instances where such clones expand and remain cohesive, often involving a large area of tissue. The main example is the movement of mutated clonal crypts through the colorectal epithelium, by the process of crypt fission. In passing, the clonal architecture of early, pre-invasive lesions is examined, often with some surprising results.
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Affiliation(s)
- S B Garcia
- Histopathology Unit, Imperial Cancer Research Fund, London, U.K
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