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Regulation of MYO18B mRNA by a network of C19MC miRNA-520G, IFN-γ, CEBPB, p53 and bFGF in hepatocellular carcinoma. Sci Rep 2020; 10:12371. [PMID: 32704163 PMCID: PMC7378193 DOI: 10.1038/s41598-020-69179-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 07/07/2020] [Indexed: 02/06/2023] Open
Abstract
MYO18B has been proposed to contribute to the progression of hepatocellular carcinoma (HCC). However, the signals that govern MYO18B transcription are not known. Here we show that, a network of C19MC miRNA-520G, IFN-γ, CEBPB and p53 transcriptional-defects promote MYO18B mRNA expression in HCCs. IFN-γ by itself suppresses MYO18B transcription, but promotes it when miRNA-520G is stably overexpressed. Similarly, CEBPB-liver-enriched activator protein (LAP) isoform overexpression suppresses MYO18B transcription but promotes transcription when the cells are treated with IFN-γ. Furthermore, miR-520G together with mutant-p53 promotes MYO18B transcription. Conversely, bFGF suppresses MYO18B mRNA irrespective of CEBPB, miR-520G overexpression or IFN-γ treatment. Finally high MYO18B expression reflects poor prognosis while high MYL5 or MYO1B expression reflects better survival of HCC patients. Thus, we identified a network of positive and negative regulators of MYO18B mRNA expression which reflects the survival of HCC patients.
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Cui G, Martin RC, Liu X, Zheng Q, Pandit H, Zhang P, Li W, Li Y. Serological biomarkers associate ultrasound characteristics of steatohepatitis in mice with liver cancer. Nutr Metab (Lond) 2018; 15:71. [PMID: 30323853 PMCID: PMC6173864 DOI: 10.1186/s12986-018-0304-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 09/20/2018] [Indexed: 01/01/2023] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of lesions ranging from steatosis to a complex pattern, nonalcoholic steatohepatitis (NASH). Ultrasonography provides important information on hepatic architecture for steatosis. NASH patients have an increased risk of hepatocellular carcinoma (HCC). Early detection of NASH is critical for clinicians to advise on necessary treatments to prevent the onset of HCC. Methods We established a NASH-HCC mouse model using diethylnitrosamine as a carcinogen to induce HCC and a high-fat diet to induce metabolic disorders. Characteristics of ultrasound imaging and potential serum biomarkers were investigated for detection of steatohepatitis and HCC in mice. Results The data suggested that ultrasound imaging of hyperechoic masses was potentially linked to the gross finding of HCC nodules, which was further confirmed by the histology. Positive correlation between serum fibroblast growth factor 15 and acoustic attenuation coefficient was found in mice with steatohepatitis. Combined with the serum markers, the increased acoustic attenuation coefficient could be a useful diagnostic parameter of ultrasound imaging for NASH detection. Conclusions This study demonstrates that a combination of serum fibroblast growth factor 15 and acoustic attenuation coefficient could be a sensitive marker for steatohepatitis and to predict carcinogenic initiation and progression of HCC in mice. These results might help for the design of ultrasound and surrogate markers in screening NASH patients who could be at risk of HCC.
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Affiliation(s)
- Guozhen Cui
- 1Department of Hepatology, Cancer Center, The First Hospital of Jilin University, No. 71. Xinmin Street, Changchun, Jilin, 130021 China
| | - Robert C Martin
- 2Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville School of Medicine, 511 S Floyd ST MDR Bldg, Louisville, KY 40202 USA
| | - Xingkai Liu
- 3Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021 China
| | - Qianqian Zheng
- Department of Pathophysiology, Basic Medicine College, China Medical University, Shenyang, 110122 China
| | - Harshul Pandit
- 2Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville School of Medicine, 511 S Floyd ST MDR Bldg, Louisville, KY 40202 USA
| | - Ping Zhang
- 3Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021 China
| | - Wei Li
- 1Department of Hepatology, Cancer Center, The First Hospital of Jilin University, No. 71. Xinmin Street, Changchun, Jilin, 130021 China
| | - Yan Li
- 2Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville School of Medicine, 511 S Floyd ST MDR Bldg, Louisville, KY 40202 USA
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Bimonte S, Leongito M, Piccirillo M, de Angelis C, Pivonello C, Granata V, Izzo F. Radio-frequency ablation-based studies on VX2rabbit models for HCC treatment. Infect Agent Cancer 2016; 11:38. [PMID: 27525037 PMCID: PMC4981963 DOI: 10.1186/s13027-016-0082-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 05/30/2016] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide with high morbidity, mortality and increasing incidence. It is of note that the main curative therapies for HCC are hepatic resection and transplantation although the majority of patients at the time of presentation are not eligible for resection or orthotopic liver transplantation (OLT) due to the underlying cirrhosis. Currently, a variety of loco-regional therapies, including radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), microwave coagulation therapy (MCT), transarterial chemoembolization (TACE) and others, have been developed as alternative treatment options for HCC. Among these techniques, RFA is currently the most widely used treatment, due to its several advantages, such as safety and efficacy. To date, the effectiveness of RFA for HCC is reduced by the presence of residual tumor as a consequence of insufficient treatment. In order to ameliorate the effects of RFA on HCC, several in vivo studies, have been performed on its application as single or in combination treatment with drugs or others loco-regional therapies, by using rabbit VX2 liver model. This represents an ideal model of liver cancers and is widely used for imaging and other experimental studies due to the rapid growth of these tumors and their similarity to human hepatocellular carcinoma. In order to elucidate the therapeutic potential of RFA with adjuvant treatments for HCC, we reviewed the latest findings on the RFA-based studies in rabbit VX2 hepatocarcinoma models.
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Affiliation(s)
- Sabrina Bimonte
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", - IRCCS, Via Mariano Semmola, 80131 Naples, Italy
| | - Maddalena Leongito
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", - IRCCS, Via Mariano Semmola, 80131 Naples, Italy
| | - Mauro Piccirillo
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", - IRCCS, Via Mariano Semmola, 80131 Naples, Italy
| | | | - Claudia Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università di Napoli Federico II, Naples, Italy
| | - Vincenza Granata
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", - IRCCS, Via Mariano Semmola, 80131 Naples, Italy
| | - Francesco Izzo
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", - IRCCS, Via Mariano Semmola, 80131 Naples, Italy
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Myeloperoxidase gene polymorphism predicts fibrosis severity in women with hepatitis C. Hum Immunol 2014; 75:766-70. [PMID: 24882572 DOI: 10.1016/j.humimm.2014.05.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 05/18/2014] [Accepted: 05/18/2014] [Indexed: 12/14/2022]
Abstract
Oxidative stress plays an important role on liver fibrosis progression in the course of hepatitis C virus (HCV) infection. Myeloperoxidase (MPO) is an enzyme released by neutrophils and macrophages, responsible for generating hypochlorous acid and reactive oxygen species (ROS) that may lead to liver injury in HCV infection. On the other hand, antioxidant enzymes such as manganese superoxide dismutase (SOD) controls ROS-mediated damage. The aim of the present study was to investigate the influence of MPO G-463A and SOD2 Ala16Val polymorphisms in the severity of liver fibrosis in individuals with chronic HCV infection. The present study included 270 patients with chronic HCV recruited from the Gastrohepatology Service of the Oswaldo Cruz University Hospital/Liver Institute of Pernambuco (Recife, Northeastern Brazil). All patients underwent liver biopsy, which was classified according METAVIR score. The SNPs were determined by real-time PCR. After multivariate analysis adjustment, the GG genotype of MPO and the presence of metabolic syndrome were independently associated with fibrosis severity in women (P = 0.025 OR 2.25 CI 1.10-4.59 and P = 0.032 OR 2.32 CI 1.07-5.01, respectively). The presence of the GG genotype seems to be a risk factor for fibrosis severity in women with HCV.
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Synthetic and natural iron chelators: therapeutic potential and clinical use. Future Med Chem 2011; 1:1643-70. [PMID: 21425984 DOI: 10.4155/fmc.09.121] [Citation(s) in RCA: 167] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Iron-chelation therapy has its origins in the treatment of iron-overload syndromes. For many years, the standard for this purpose has been deferoxamine. Recently, considerable progress has been made in identifying synthetic chelators with improved pharmacologic properties relative to deferoxamine. Most notable are deferasirox (Exjade(®)) and deferiprone (Ferriprox(®)), which are now available clinically. In addition to treatment of iron overload, there is an emerging role for iron chelators in the treatment of diseases characterized by oxidative stress, including cardiovascular disease, atherosclerosis, neurodegenerative diseases and cancer. While iron is not regarded as the underlying cause of these diseases, it does play an important role in disease progression, either through promotion of cellular growth and proliferation or through participation in redox reactions that catalyze the formation of reactive oxygen species and increase oxidative stress. Thus, iron chelators may be of therapeutic benefit in many of these conditions. Phytochemicals, many of which bind iron, may also owe some of their beneficial properties to iron chelation. This review will focus on the advances in iron-chelation therapy for the treatment of iron-overload disease and cancer, as well as neurodegenerative and chronic inflammatory diseases. Established and novel iron chelators will be discussed, as well as the emerging role of dietary plant polyphenols that effectively modulate iron biochemistry.
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Jin F, Xiong WJ, Jing JC, Feng Z, Qu LS, Shen XZ. Evaluation of the association studies of single nucleotide polymorphisms and hepatocellular carcinoma: a systematic review. J Cancer Res Clin Oncol 2011; 137:1095-104. [PMID: 21240526 DOI: 10.1007/s00432-010-0970-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Accepted: 12/20/2010] [Indexed: 02/07/2023]
Abstract
PURPOSE For decades of years, hundreds of candidate gene-based association studies explored the relationship between single nucleotide polymorphisms (SNPs) and hepatocellular carcinoma (HCC). There was no systematic review summarized the results of these association studies of candidate SNPs and HCC to date. In order to summarize the results of the association studies, we conducted a concise systematic review. METHODS By searching Pubmed database before October 2010, we reviewed all the association studies about candidate SNPs and HCC. If the eligible study number on a given SNP was more than three, we conducted a meta-analysis. We reported here only the overall positive-association results with statistical significance and evaluated the reliability of the associations by using false-positive report probability (FPRP) analysis and the Venice guidelines on genetic epidemiology studies. RESULTS Six SNPs of five genes (rs1800562 of HFE, rs17868323 and rs11692021 of UGT1A7, rs2279744 of MDM2, rs1143627 of IL-1B, and rs4880 of MnSOD) showed overall significant associations with HCC. The eligible number of the studies varied from three to nine. Two SNPs (rs1800562 of HFE and rs2279744 of MDM2) passed the FPRP threshold (FPRP < 0.20). According to the Venice guidelines, the associations between the two SNPs (rs1800562 and rs2279744) and HCC were of moderate evidence. CONCLUSIONS Two SNPs (rs1800562 of HFE and rs2279744 of MDM2) were associated with HCC with moderate epidemiological evidence and deserve further study and additional biological and clinical assessment.
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Affiliation(s)
- Fei Jin
- Department of Gastroenterology, Shanghai Xuhui Central Hospital, Shanghai, China.
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Low temperature of radiofrequency ablation at the target sites can facilitate rapid progression of residual hepatic VX2 carcinoma. J Transl Med 2010; 8:73. [PMID: 20667141 PMCID: PMC2917410 DOI: 10.1186/1479-5876-8-73] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Accepted: 07/29/2010] [Indexed: 12/13/2022] Open
Abstract
Background Rapid progression of residual tumor after radiofrequency ablation (RFA) of hepatocellular carcinoma has been observed increasingly. However, its underlying mechanisms remain to be clarified. The present study was designed to determine whether low temperature of RFA at the target sites facilitates rapid progression of residual hepatic VX2 carcinoma and to clarify the possible underlying mechanisms. Methods The residual VX2 hepatoma model in rabbits was established by using RFA at 55, 70 and 85°C. Rabbits that were implanted with VX2 hepatoma but did not receive RFA acted as a control group. The relationship between rapid progression of residual hepatic VX2 carcinoma and low temperature of RFA at the target sites was carefully evaluated. A number of potential contributing molecular factors, such as proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 9 (MMP-9), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and Interleukin-6 (IL-6) were measured. Results The focal tumor volume and lung metastases of RFA-treated rabbits increased significantly compared with the control group (P < 0.05), and the greatest changes were seen in the 55°C group (P < 0.05). Expression of PCNA, MMP-9, VEGF, HGF and IL-6 in tumor tissues increased significantly in the RFA-treated groups compared with the control group, and of the increases were greatest in the 55°C group (P < 0.05). These results were consistent with gross pathological observation. Tumor re-inoculation experiments confirmed that low temperature of RFA at the target sites facilitated rapid progression of residual hepatic VX2 carcinoma. Conclusions Insufficient RFA that is caused by low temperature at the target sites could be an important cause of rapid progression of residual hepatic VX2 carcinoma. Residual hepatic VX2 carcinoma could facilitate its rapid progression through inducing overexpression of several molecular factors, such as PCNA, MMP-9, VEGF, HGF and IL-6.
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Abstract
The underlying liver diseases that put patients at risk for the development of hepatocellular carcinoma (HCC) are well known. However, it is equally well known that not all patients with these conditions will develop HCC. Therefore within the disease groups (hepatitis B, cirrhosis, etc.,) there are other factors that indicate greater or lesser risk. Some markers of risk are common to all causes of HCC, such as cellular dysplasia, advancing age and male gender. Others factors are specific to individual diseases. This has been well established for hepatitis B in which viral load, genotype and antigen status are major contributors to increased risk of HCC. For both hepatitis B and hepatitis C attempts have been made to identify those individuals at greatest risk using data from large cohort studies. In addition to the common causes of liver disease that are recognized to be causes of HCC non-alcoholic fatty liver disease and possibly diabetes are newly emerging risk factors.
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Nahon P, Sutton A, Rufat P, Ziol M, Akouche H, Laguillier C, Charnaux N, Ganne-Carrié N, Grando-Lemaire V, N'Kontchou G, Trinchet JC, Gattegno L, Pessayre D, Beaugrand M. Myeloperoxidase and superoxide dismutase 2 polymorphisms comodulate the risk of hepatocellular carcinoma and death in alcoholic cirrhosis. Hepatology 2009; 50:1484-93. [PMID: 19731237 DOI: 10.1002/hep.23187] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
UNLABELLED Alcohol increases reactive oxygen species (ROS) formation in hepatocyte mitochondria and by reduced nicotinamide adenine dinucleotide phosphate oxidases and myeloperoxidase (MPO) in Kupffer cells and liver-infiltrating neutrophils. Manganese superoxide dismutase (MnSOD) converts superoxide anion into hydrogen peroxide, which, unless detoxified by glutathione peroxidase or catalase (CAT), can form the hydroxyl radical with iron. Our aim was to determine whether Ala16Val-superoxide dismutase 2 (SOD2), G-463A-MPO, or T-262C-CAT dimorphisms modulate the risks of hepatocellular carcinoma (HCC) and death in alcoholic cirrhosis. Genotypes and the hepatic iron score were assessed in 190 prospectively followed patients with alcoholic cirrhosis. During follow-up (61.1 +/- 2.7 months), 51 patients developed HCC, and 71 died. The T-262C-CAT dimorphism did not modify hepatic iron, HCC, or death. The GG-MPO genotype did not modify iron but increased the risks of HCC and death. The hazard ratio (HR) was 4.7 (2.1-10.1) for HCC and 3.6 (1.9-6.7) for death. Carriage of one or two Ala-SOD2 allele(s) was associated with higher liver iron scores and higher risks of HCC and death. The 5-year incidence of HCC was 34.4% in patients with both the GG-MPO genotype and one or two Ala-SOD2 alleles, 5.1% in patients with only one of these two traits, and 0% in patients with none of these traits. Corresponding 5-year death rates were 37.6%, 11.6%, and 5%. CONCLUSION The combination of the GG-MPO genotype (leading to high MPO expression) and at least one Ala-SOD2 allele (associated with high liver iron score) markedly increased the risks of HCC occurrence and death in patients with alcoholic cirrhosis.
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Affiliation(s)
- Pierre Nahon
- Service d'Hépatologie, Hôpital Jean Verdier, AP-HP, Bondy, France.
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10
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Nagata H, Hatano E, Tada M, Murata M, Kitamura K, Asechi H, Narita M, Yanagida A, Tamaki N, Yagi S, Ikai I, Matsuzaki K, Uemoto S. Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor- suppression in rat hepatocellular carcinoma. Hepatology 2009; 49:1944-53. [PMID: 19418558 DOI: 10.1002/hep.22860] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
UNLABELLED Transforming growth factor beta (TGF-beta) signaling involves both tumor-suppression and oncogenesis. TGF-beta activates the TGF-beta type I receptor (TbetaRI) and c-Jun N-terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become COOH-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TbetaRI-dependent pSmad3C transmits a tumor-suppressive TGF-beta signal, while JNK-dependent pSmad3L promotes carcinogenesis in human chronic liver disorders. The aim of this study is to elucidate how SP600125, a JNK inhibitor, affected rat hepatocellular carcinoma (HCC) development, while focusing on the domain-specific phosphorylation of Smad3. The rats received subcutaneous injections of either SP600125 or vehicle 11 times weekly together with 100 ppm N-diethylnitrosamine (DEN) administration for 56 days and were sacrificed in order to evaluate HCC development 28 days after the last DEN administration. The number of tumor nodules greater than 3 mm in diameter and the liver weight/body weight ratio were significantly lower in the SP600125-treated rats than those in the vehicle-treated rats (7.9 +/- 0.8 versus 17.7 +/- 0.9: P < 0.001; 6.3 +/- 1.2 versus 7.1 +/- 0.2%: P < 0.05). SP600125 significantly prolonged the median survival time in rats with DEN-induced HCC (113 versus 97 days: log-rank P = 0.0018). JNK/pSmad3L/c-Myc was enhanced in the rat hepatocytes exposed to DEN. However, TbetaRI/pSmad3C/p21(WAF1) was impaired as DEN-induced HCC developed and progressed. The specific inhibition of JNK activity by SP600125 suppressed pSmad3L/c-Myc in the damaged hepatocytes and enhanced pSmad3C/p21(WAF1), acting as a tumor suppressor in normal hepatocytes. CONCLUSION Administration of SP600125 to DEN-treated rats shifted hepatocytic Smad3-mediated signal from oncogenesis to tumor suppression, thus suggesting that JNK could be a therapeutic target of human HCC development and progression.
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Affiliation(s)
- Hiromitsu Nagata
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Pires VS, Gaboriau F, Guillon J, Nascimento S, Dassonville A, Lescoat G, Desplat V, Rochette J, Jarry C, Sonnet P. Modulation of cell proliferation in rat liver cell cultures by new calix[4]arenes. J Enzyme Inhib Med Chem 2008; 21:261-70. [PMID: 16918073 DOI: 10.1080/14756360600700384] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
Cell cycle progression is dependent on intracellular iron level and chelators lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of new synthetic calix[4]arene podands bearing two aspartic/glutamic acid, ornithine groups or hydrazide function at the lower rim, designed as potential iron chelators. The synthesis only afforded calix[4]arenes in the cone conformation. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670A (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in the rat hepatoma cell line Fao by measuring mitochondrial succinate dehydrogenase activity. Their cytotoxicity was evaluated by extracellular LDH activity. Preliminary results indicated that among all tested compounds, monohydrazidocalix[4]arene 2 which is not cytotoxic in Fao cells exhibits interesting antiproliferative activity. This effect, independent on iron depletion, remains to be further explored. Moreover, it also shows that new substituted calix[4]arenes could open the way to new valuable medicinal chemistry scaffolding.
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Affiliation(s)
- Viviane Silva Pires
- EA 3901, DMAG, UFR de Pharmacie et de Médecine, Université de Picardie Jules Verne, 1 rue des Louvels, 80037 Amiens, France
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Mahmood S, Togawa K, Kawanaka M, Niiyama G, Yamada G. An analysis of risk factors for developing Hepatocellular carcinoma in a group of Hepatitis C patients with stage 3 fibrosis following interferon therapy. Cancer Inform 2008; 6:381-7. [PMID: 19259418 PMCID: PMC2623298 DOI: 10.4137/cin.s644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The risk of Hepatocellular carcinoma (HCC) is high in HCV-infected patients who have biochemically and histologically active chronic hepatitis. To observe the long prognosis of Chronic Hepatitis C (CHC) patients with stage 3 fibrosis (F3), 55 CHC patients after initial Interferon (IFN) therapy were followed up for up to 12 years (average 9.8 ± 2.3 years). According to the annual average alanine aminotransferase (ALT) levels, patients were grouped into, low (ALT ≦ 30 IU/l); moderate (ALT >30 <80 IU/l) and high (ALT ≧ 80 IU/l) ALT groups. Eleven patients were re-treated with IFN. During the follow-up period of 12 years, HCC developed in 26 patients with an average annual incidence of 3.9%. Biochemical responders to initial IFN therapy (n = 8) and those re-treated with IFN (n = 10), except 1, did not develop HCC. Cox regression analysis to evaluate risk factors for HCC occurrence, found development of Liver Cirrhosis within 3 years of initial IFN therapy(P = 0.05) and the 3 year annual average ALT post initial IFN therapy (P = 0.033) to be significant. The 12 year annual average ALT was also found to be significantly related to HCC occurrence (P = 0.016), on univariate analysis. Patients belonging to the continuously low ALT group (ALT ≦ 30 IU/l for ≧3 years), did not develop HCC or receive IFN re-treatment. In CHC patients with F3, after initial IFN therapy, keeping ALT continuously low, below 30 IU/l for 3 years or more seems important. Continuing treatment with anti-inflammatory drugs along with subsequent IFN re-treatment may prevent or delay HCC even in elderly patients.
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Affiliation(s)
- Sabina Mahmood
- Department of Internal Medicine, Center for Liver Disease, Kawasaki Hospital, Kawasaki Medical School, Okayama City, Okayama, Japan.
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Abstract
This article reviews methodological issues around screening for hepatocellular carcinoma, and discusses selection of the at-risk group, which screening test to use, and how frequently it should be applied. Screening of patients at risk for hepatocellular carcinoma should be undertaken using ultrasonography applied at six-month intervals. Patients at risk include all those with cirrhosis, and certain non-cirrhotic patients withchronic hepatitis B. In this population, screening has been shown to reduce disease-specific mortality. Although data do not exist for other populations, screening is nonetheless advised because small cancers can be cured with appreciable frequency.
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Morinaga S, Tarao K, Yamamoto Y, Nakamura Y, Rino Y, Miyakawa K, Ohkawa S, Akaike M, Sugimasa Y, Takemiya S. Overexpressed cyclo-oxygenase-2 in the background liver is associated with the clinical course of hepatitis C virus-related cirrhosis patients after curative surgery for hepatocellular carcinoma. J Gastroenterol Hepatol 2007; 22:1249-55. [PMID: 17688665 DOI: 10.1111/j.1440-1746.2006.04367.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND The probable role of cyclo-oxygenase-2 (COX-2) in the development of hepatocellular carcinoma (HCC) in patients with chronic liver diseases has been accepted to be relevant. The purpose of the present study was to determine whether overexpressed COX-2 in the background liver affects the clinical course of hepatitis C virus (HCV)-related cirrhosis patients after curative surgery for HCC. METHODS Twenty-nine clinical stage I HCC patients with HCV-related cirrhosis, who underwent curative surgery, were enrolled in the present study (22 men and seven women, age range 53-73 years; follow-up period; range 22-159 months, median 61 months). The COX-2 expression in the cirrhotic liver was examined by immunohistochemistry using the avidin-biotin-peroxidase complex technique on paraffin-embedded formalin-fixed tissue. The COX-2 expression was scored, then correlated with monitored alanine aminotransferase (ALT) levels during the follow-up period after surgery, response to alternative therapy aiming to improve elevated ALT levels, and recurrence/survival after surgery. RESULTS The COX-2 expression scores were significantly higher in the high-ALT group than in the low-ALT group (Mann-Whitney, P = 0.010), and were significantly higher in non-responders to the alternative therapy than in responders (Mann-Whitney, P = 0.028). The higher COX-2 expression in the cirrhotic liver was the significant independent risk factor for residual liver recurrence (Cox multivariate analysis, P = 0.014), but not for survival. CONCLUSIONS Overexpressed COX-2 in the background liver may play an important role in prolonged acceleration of necroinflammation, resistance to the alternative therapy, and recurrence/new development of HCC in HCV-related cirrhosis patients.
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Affiliation(s)
- Soichiro Morinaga
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Asahikum, Japan.
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Gaboriau F, Laupen-Chassay C, Pasdeloup N, Pierre JL, Brissot P, Lescoat G. Modulation of cell proliferation and polyamine metabolism in rat liver cell cultures by the iron chelator O-trensox. Biometals 2006; 19:623-32. [PMID: 16944279 DOI: 10.1007/s10534-006-6888-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2005] [Accepted: 01/21/2006] [Indexed: 10/24/2022]
Abstract
The antiproliferative effects of the iron chelator O-trensox and the ornithine-decarboxylase (ODC) inhibitor alpha-difluoromethylornithine (DFMO) were characterized in the rat hepatoma cell line FAO, the rat liver epithelial cell line (RLEC) and the primary rat hepatocyte cultures stimulated by EGF. We observed that O-trensox and DFMO decreased cell viabilty and DNA replication in the three culture models. The cytostatic effect of O-trensox was correlated to a cytotoxicity, higher than for DFMO, and to a cell cycle arrest in G0/G1 or S phases. Moreover, O-trensox and DFMO decreased the intracellular concentration of spermidine in the three models without changing significantly the spermine level. We concluded that iron, but also polyamine depletion, decrease cell growth. However, the drop in cell proliferation obtained with O-trensox was stronger compared to DFMO effect. Altogether, our data provide insights that, in the three rat liver cell culture models, the cytostatic effect of the iron chelator O-trensox may be the addition of two mechanisms: iron and polyamine depletion.
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Azzaroli F, Colecchia A, Colecchi A, Lodato F, Trerè D, Bacchi Reggiani ML, Festi D, Prati GM, Accogli E, Casanova S, Derenzini M, Roda E, Mazzella G. A statistical model predicting high hepatocyte proliferation index and the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis. Aliment Pharmacol Ther 2006; 24:129-36. [PMID: 16803611 DOI: 10.1111/j.1365-2036.2006.02955.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Incidence of hepatocellular carcinoma in hepatitis C virus-related cirrhosis is 4% per year. Although cost-effective, current screening could be improved. AIM To develop a statistical model including non-invasive parameters able to identify patients at high risk of developing hepatocellular carcinoma. METHODS One hundred and fifty-eight patients (73F:85M) with compensated chronic hepatitis C virus liver disease underwent evaluation, including argyrophilic nucleolar organizer regions proliferation index, and were followed up for 56.18 +/- 1.44 months. RESULTS Fifty-six patients had chronic hepatitis without cirrhosis and low argyrophilic nucleolar organizer regions proliferation index (< or =25%), 65 had hepatitis C virus-related cirrhosis and low argyrophilic nucleolar organizer regions proliferation index and 37 had hepatitis C virus-related cirrhosis and high argyrophilic nucleolar organizer regions proliferation index (>25%). Groups were similar for gender and viral genotype distribution. None of the patients with chronic hepatitis without cirrhosis developed hepatocellular carcinoma, compared with 6.1% of low argyrophilic nucleolar organizer regions proliferation index and 30.6% of high argyrophilic nucleolar organizer regions proliferation index (P = 0.002). By multivariable logistic regression analysis, the following parameters were independently associated with hepatocellular carcinoma development and used for the development of the statistical model: platelets (OR 0.98), gamma-globulins (OR 0.111), alanine aminotransferase/aspartate aminotransferase ratio (OR 0.07), serum ferritin (OR 1.0) and ultrasonographic pattern (coarse OR 2.9, coarse nodular OR 10.12). The statistical model properly allocated 95.9% of patients with low argyrophilic nucleolar organizer regions proliferation index and 72.2% of patients with high argyrophilic nucleolar organizer regions proliferation index. CONCLUSIONS The model, to be validated in large prospective studies, may help tailoring screening according to the risk of hepatocellular carcinoma development.
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Affiliation(s)
- F Azzaroli
- Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy.
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17
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Cheung PY, Zhang Q, Zhang YO, Bai GR, Lin MCM, Chan B, Fong CC, Shi L, Shi YF, Chun J, Kung HF, Yang M. Effect of WeiJia on carbon tetrachloride induced chronic liver injury. World J Gastroenterol 2006; 12:1912-7. [PMID: 16609998 PMCID: PMC4087517 DOI: 10.3748/wjg.v12.i12.1912] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [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 WeiJia on chronic liver injury using carbon tetrachloride (CCl4) induced liver injury animal model.
METHODS: Wistar rats weighing 180-220g were randomly divided into three groups: normal control group (Group A), CCl4 induced liver injury control group (Group B) and CCl4 induction with WeiJia treatment group (Group C). Each group consisted of 14 rats. Liver damage and fibrosis was induced by subcutaneous injection with 40% CCl4 in olive oil at 3 mL/kg body weight twice a week for eight weeks for Groups B and C rats whereas olive oil was used for Group A rats. Starting from the third week, Group C rats also received daily intraperitoneal injection of WeiJia at a dose of 1.25 μg/kg body weight. Animals were sacrificed at the fifth week (4 male, 3 female), and eighth week (4 male, 3 female) respectively. Degree of fibrosis were measured and serological markers for liver fibrosis and function including hyaluronic acid (HA), type IV collagen (CIV), γ-glutamyl transferase (γ-GT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Alpha smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) immunohistochemistry were also performed.
RESULTS: CCl4 induction led to the damage of liver and development of fibrosis in Group B and Group C rats when compared to Group A rats. The treatment of WeiJia in Group C rats could reduce the fibrosis condition significantly compared to Group B rats. The effect could be observed after three weeks of treatment and was more obvious after eight weeks of treatment. Serum HA, CIV, ALT, AST and γ-GT levels after eight weeks of treatment for Group C rats were 58±22 µg/L (P<0.01), 57±21 µg/L (P<0.01), 47±10 U/L (P<0.01), 139±13 U/L (P<0.05) and 52±21 U/L (P>0.05) respectively, similar to normal control group (Group A), but significantly different from CCl4 induced liver injury control group (Group B). An increase in PCNA and decrease in α-SMA expression level was also observed.
CONCLUSION: WeiJia could improve liver function and reduce liver fibrosis which might be through the inhibition of stellate cell activity.
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Affiliation(s)
- Pik-Yuen Cheung
- Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong SAR, China
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18
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Sutton A, Nahon P, Pessayre D, Rufat P, Poiré A, Ziol M, Vidaud D, Barget N, Ganne-Carrié N, Charnaux N, Trinchet JC, Gattegno L, Beaugrand M. Genetic Polymorphisms in Antioxidant Enzymes Modulate Hepatic Iron Accumulation and Hepatocellular Carcinoma Development in Patients with Alcohol-Induced Cirrhosis. Cancer Res 2006; 66:2844-52. [PMID: 16510607 DOI: 10.1158/0008-5472.can-05-2566] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Manganese superoxide dismutase (MnSOD) converts the superoxide anion into H(2)O(2), which, unless it is detoxified by glutathione peroxidase 1 (GPx1), can increase hepatic iron and can react with iron to form genotoxic compounds. We investigated the role of Ala/Val-MnSOD and Pro/Leu-GPx1 polymorphisms on hepatic iron accumulation and hepatocellular carcinoma development in patients with alcoholic cirrhosis. Genotypes were determined in 162 alcoholic patients with cirrhosis but without hepatocellular carcinoma initially, who were prospectively followed up for hepatocellular carcinoma development. We found that patients with two Val-MnSOD alleles (slow H(2)O(2) production) and two Pro-GPx1 alleles (presumably quick H(2)O(2) detoxification) had a lower risk of hepatocellular carcinoma development than other patients (chi(2) trend test, P = 0.001; log-rank, P = 0.0009). Indeed, hepatocellular carcinoma percentage was 0% in subjects with this "2Val-MnSOD/2Pro-GPx1" genotype versus 16%, 27%, and 32% in "2Val-MnSOD/1or2Leu-GPx1," "1or2Ala-MnSOD/2Pro-GPx1," and "1or2Ala-MnSOD/1or2Leu-GPx1" patients, respectively. The percentage of patients with stainable hepatic iron increased progressively with these genotypic associations: 22%, 28%, 50%, and 53%, respectively (chi(2) trend test, P = 0.005). Stainable iron was a risk factor for hepatocellular carcinoma (log-rank, P = 0.0002; relative risk, 3.40). In conclusion, polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in French alcoholic patients with cirrhosis.
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Affiliation(s)
- Angela Sutton
- UPRES 3410, UFR Santé, Médecine et Biologie Humaine, Université Paris XIII, Bobigny, France.
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19
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Koskinas J, Petraki K, Kavantzas N, Rapti I, Kountouras D, Hadziyannis S. Hepatic expression of the proliferative marker Ki-67 and p53 protein in HBV or HCV cirrhosis in relation to dysplastic liver cell changes and hepatocellular carcinoma. J Viral Hepat 2005; 12:635-41. [PMID: 16255765 DOI: 10.1111/j.1365-2893.2005.00635.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
To evaluate hepatic expression of the nuclear proliferative marker Ki-67 and the p53 oncoprotein in hepatitis B virus (HBV)/HCV cirrhosis in relation to dysplastic liver cell changes and hepatocellular carcinoma (HCC). We studied needle liver biopsies from 107 patients with cirrhosis and no HCC (52 HBV, 55 HCV) who had been assessed for protocol studies, and 57 cirrhotic patients with HCC (40 HBV, 17 HCV). We evaluated small and large cell dysplastic changes along with the expression of Ki-67 and p53 by immunohistochemistry. The labelling index (LI) was defined as the proportion (%) of positive-stained nuclei of the 500 measured. Large and small cell dysplastic changes were observed in 12 and 9% of specimens respectively. Only small cell changes were associated with Ki-67 expression. Ki-67 LI was 5.50 +/- 5.7 in cirrhosis (13.90 +/- 3.84 in those with small cell dysplastic changes vs 4.64 +/- 4.98 in those without, P < 0.01), 10.2 +/- 5.95 in cirrhosis with HCC (P < 0.05) and 18.56 +/- 10 in HCC (P < 0.01). Neither the presence of small cell dysplastic changes nor the expression of Ki-67 was related to severity or aetiology of cirrhosis. Expression of p53 was observed in 30% of the non-tumorous and in 53% of the neoplastic tissue obtained from patients with HCC, with no differences between HCV and HBV. Ki-67 and p53 expression was associated with the tumour grade (P < 0.001). Our observations clearly demonstrate the association between the proliferation activity and the morphological changes in the cirrhotic liver from the non-dysplastic to dysplastic lesion to HCC. They also support the hypothesis that p53 alterations are a rather late event in carcinogenesis and related to HCC grade. And finally, they suggest that the final steps of hepatocarcinogenesis are common and independent of the aetiology of the chronic viral infection.
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Affiliation(s)
- J Koskinas
- Second Department of Medicine, Athens University, Athens, Greece.
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20
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Affiliation(s)
- Jordi Bruix
- BCLC Group. Liver Unit. Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
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21
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Matsuda Y, Yamagiwa S, Takamura M, Honda Y, Ishimoto Y, Ichida T, Aoyagi Y. Overexpressed Id-1 is associated with a high risk of hepatocellular carcinoma development in patients with cirrhosis without transcriptional repression of p16. Cancer 2005; 104:1037-44. [PMID: 15999366 DOI: 10.1002/cncr.21259] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inhibitor of differentiation/DNA binding protein 1 (Id-1) plays a pivotal role in the regulation of cell proliferation and carcinogenesis via inhibiting basic helix-loop-helix (HLH) transcription factors. Recently, Id-1 was found to repress p16 in tumorous tissue specimens including hepatocellular carcinoma (HCC), but its relevance in precancerous liver tissues is unknown. METHODS Id-1 expression in the liver tissue specimens of 112 patients with cirrhosis without HCC was studied by immunohistochemical analysis. Correlations were investigated between Id-1 expression and clinicopathologic features, the status of p16, and the risk of HCC occurrence. RESULTS A high expression of Id-1 was observed in 42 patients (38%). The level of Id-1 expression was not associated with clinical standard parameters or the status of p16 in cirrhotic tissue specimens. The cumulative incidence of HCC development was significantly higher in a group of patients with high Id-1 expression (P = 0.0008). Multivariate analysis revealed that increased Id-1 expression is an independent significant factor for the risk of HCC development in patients with cirrhosis (relative risk = 2.75, P = 0.003). CONCLUSIONS The results of the current study suggested that increased expression of Id-1 may play an important role in the early step of hepatocarcinogenesis, and might serve as a useful marker for determining patients with cirrhosis with a high risk of HCC occurrence.
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Affiliation(s)
- Yasunobu Matsuda
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Japan.
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22
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Abstract
There is currently no evidence that screening patients at risk for hepatocellular carcinoma reduces mortality from the disease. Nonetheless, screening is widely practiced. Screening is a process that includes selecting patients, applying screening tests, deciding on recall policies, and subsequently proving or disproving the presence of cancer. The literature on screening for hepatocellular carcinoma is confusing at best, and does not adequately consider the many biases that result from uncontrolled and retrospective studies. Nonetheless, screening can be justified because it is likely that mortality is decreased by adequate treatment of small cancers, particularly in the era of liver transplantation. False-positive screening test results are common. Once an abnormal screening result is obtained there is little guidance from the literature as to how patients should be investigated further, nor about how to determine whether the screening test result was a false-positive. This should at minimum include short interval follow-up with CT scans and MRI's.
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Affiliation(s)
- Morris Sherman
- University of Toronto and Toronto General Hospital, 200 Elizabeth Street, Toronto, Ont., Canada M5G 2C4.
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23
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Azzaroli F, Accogli E, Nigro G, Trere D, Giovanelli S, Miracolo A, Lodato F, Montagnani M, Tamé M, Colecchia A, Mwangemi C, Festi D, Roda E, Derenzini M, Mazzella G. Interferon plus ribavirin and interferon alone in preventing hepatocellular carcinoma: A prospective study on patients with HCV related cirrhosis. World J Gastroenterol 2004; 10:3099-102. [PMID: 15457551 PMCID: PMC4611249 DOI: 10.3748/wjg.v10.i21.3099] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To determine the role of interferon (IFN) with or without ribavirin in preventing or delaying hepatocellular carcinoma (HCC) development in patients with hepatitis C virus (HCV) related cirrhosis. Data on the preventive effect of IFN plus ribavirin treatment are lacking.
METHODS: A total of 101 patients (62 males and 39 females, mean age 55.1 ± 1.4 years) with histologically proven HCV related liver cirrhosis plus compatible biochemistry and ultrasonography were enrolled in the study. Biochemistry and ultrasonography were performed every 6 mo. Ultrasound guided liver biopsy was performed on all detected focal lesions. Follow-up lasted for 5 years. Cellular proliferation, evaluated by measuring Ag-NOR proteins in hepatocytes nuclei, was expressed as AgNOR-Proliferative index (AgNOR-PI) (cut-off = 2.5). Forty-one patients (27 males, 14 females) were only followed up after the end of an yearly treatment with IFN-alpha2b (old treatment control group = OTCG). Sixty naive patients were stratified according to sex and AgNOR-PI and then randomized in two groups: 30 were treated with IFN-alpha2b + ribavirin (treatment group = TG), the remaining were not treated (control group = CG). Nonresponders (NR) or relapsers in the TG received further IFN/ribavirin treatments after a 6 mo of withdrawal.
RESULTS: AgNOR-PI was significantly lowered by IFN (P < 0.001). HCC incidence was higher in patients with AgNOR-PI > 2.5 (26% vs 3%, P < 0.01). Two NR in the OTCG, none in the TG and 9 patients in the CG developed HCC during follow-up. The Kaplan-Mayer survival curves showed statistically significant differences both between OTCG and CG (P < 0.004) and between TG and CG (P < 0.003).
CONCLUSION: IFN/ribavirin treatment associated with re-treatment courses of NR seems to produce the best results in terms of HCC prevention. AgNOR-PI is a useful marker of possible HCC development.
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Affiliation(s)
- Francesco Azzaroli
- Department of Internal Medicine, University of Bologna, Via Massarenti 9, 40138 Bologna.
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24
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Abstract
Hepatocellular carcinoma is an increasingly common clinical problem. Investigators have begun to understand aspects of the pathogenesis of the tumor, mainly from a morphologic point of view. Preneoplastic lesions and early cancer may be difficult to distinguish radiologically. Nonetheless, programs for surveillance of liver cancer have been developed. Little uniformity exists in methods of surveillance, and even less in methods of investigation and follow-up after an abnormal result is obtained. This article attempts to bring some rigor to the understanding of hepatocellular carcinoma.
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25
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Gaboriau F, Chantrel-Groussard K, Rakba N, Loyer P, Pasdeloup N, Hider RC, Brissot P, Lescoat G. Iron mobilization, cytoprotection, and inhibition of cell proliferation in normal and transformed rat hepatocyte cultures by the hydroxypyridinone CP411, compared to CP20: a biological and physicochemical study. Biochem Pharmacol 2004; 67:1479-87. [PMID: 15041465 DOI: 10.1016/j.bcp.2003.12.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2003] [Accepted: 12/07/2003] [Indexed: 11/18/2022]
Abstract
The present study analyzes the iron mobilization, the cytoprotective, and the antiproliferative effects of the lipophilic hydroxypyridinone CP411, in comparison with the hydrophilic chelator CP20 or deferiprone used in the treatment of iron overload. Primary rat hepatocyte cultures and the rat hepatoma cell line Fao were used. Chelator cell uptake was evaluated by mass spectrometry in the two models. This method was also used to investigate the stability of the chelators in an acellular system as well as their scavenging and chelating effects against the hydroxyl radical generated by the Fenton reaction. The iron mobilization and the cytoprotective effects of the chelators were evaluated in primary cultures by measuring respectively 55Fe and lactate dehydrogenase release in the culture medium. The antiproliferative effect of the chelators was studied using the Fao cell line and measuring DNA synthesis by thymidine incorporation and DNA content by flow cytometry. We observed that CP411 entered the hepatocytes and the Fao cells respectively 4 and 13 times more than CP20. CP411 was 2.5 times more effective than CP20 to mobilize iron from preloaded hepatocytes. Pretreatment of the hepatocytes with CP20 or CP411 decreased the toxic effect of iron and CP411 was 1.6 times more effective than CP20. A dose-dependent decrease of DNA synthesis, correlated to an accumulation of cells in S phase, was observed in the Fao cell line in the presence of CP411, while CP20 was without effect. CP411 effect was inhibited by addition of iron simultaneously with the chelator, the addition of Zn or Cu was without effect. The inhibitory effect of CP411 was reversible since, 24hr after removal of the chelator, DNA replication reached the control level. The results show that CP411 is more efficient to protect the hepatocyte from the toxic effect of iron load and to inhibit tumor cell proliferation. Its higher efficiency may result from its better cell uptake since equimolar solutions of the two chelators in an acellular system exhibit the same ability to inhibit the Fenton reaction.
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Affiliation(s)
- François Gaboriau
- Inserm U 522, Equipe: "Foie, fer et autres métaux", CHU de Rennes, Hôpital Pontchaillou, Rennes, France.
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26
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Rudnick DA, Liao Y, An JK, Muglia LJ, Perlmutter DH, Teckman JH. Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency. Hepatology 2004; 39:1048-55. [PMID: 15057909 DOI: 10.1002/hep.20118] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
alpha-1-Antitrypsin (alpha1-AT) deficiency is the most common cause of metabolic pediatric liver disease. Hepatocellular injury is caused by toxicity of the mutant alpha-1-antitrypsin Z (alpha1-ATZ) molecule retained within hepatocytes. In these studies, we used the PiZ transgenic mouse model of alpha1-AT deficiency to examine hepatocellular proliferation in response to chronic liver injury resulting from this metabolic disease. The results showed increased hepatocellular proliferation and caspase 9 activation in male PiZ mice compared with female PiZ and wild-type mice. Hepatic alpha1-AT mRNA and protein expression also were increased in male PiZ mice, suggesting that greater hepatocellular proliferation and caspase activation in males results from increased hepatotoxicity associated with greater intracellular alpha1-ATZ accumulation. Testosterone treatment of female PiZ mice increased alpha1-ATZ expression and hepatocellular proliferation to a level comparable with that in males. In PiZ mice, hepatocytes devoid of intracellular alpha1-AT globules had a proliferative advantage compared with globule-containing hepatocytes. However, this advantage is relative because both globule-containing and globule-devoid hepatocytes exhibited comparable proliferation after partial hepatectomy. In conclusion, these data indicate that intracellular retention of mutant alpha1-ATZ is associated with a regenerative stimulus leading to increased hepatocellular proliferation, that gender-specific signals influence the degree of alpha1-AT expression and associated hepatic injury, and that hepatocytes devoid of alpha1-ATZ have a proliferative advantage over cells that accumulate the mutant protein. This selective proliferation suggests that hepatocellular transplantation may be applicable for treatment of this and other slowly progressive metabolic liver diseases.
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Affiliation(s)
- David A Rudnick
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
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27
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Kashiwagi K, Furusyo N, Kubo N, Nakashima H, Nomura H, Kashiwagi S, Hayashi J. A prospective comparison of the effect of interferon-alpha and interferon-beta treatment in patients with chronic hepatitis C on the incidence of hepatocellular carcinoma development. J Infect Chemother 2004; 9:333-40. [PMID: 14691655 DOI: 10.1007/s10156-003-0271-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2003] [Accepted: 07/28/2003] [Indexed: 01/04/2023]
Abstract
To investigate differences in the effect of interferon (IFN) -alpha and IFN-beta treatment for hepatitis C on hepatocellular carcinoma (HCC) development, we prospectively followed 351 consecutive patients (median age, 56.6 years; mean follow-up, 5.7 +/- 2.6 years) with chronic hepatitis C virus (HCV) viremia. Of 260 IFN-alpha and 91 IFN-beta treated patients, 17 (6.5%) and 4 (4.4%), respectively, developed HCC. Virological response (VR) was defined as persistent HCV RNA disappearance from serum, and biochemical response (BR) as persistent alanine aminotransferase (ALT) normalization after treatment. No significant between-group differences in HCC development were found between those with and without VR. Although the HCC development rate in patients without BR was significantly higher than that in patients with BR in the IFN-alpha group (11.4% and 0.8%; P << 0.05), no significant difference was found in the IFN-beta group (6.3% and 2.3%). Similar rates of HCC development were found in patients with chronic HCV viremia treated with either IFN-alpha or IFN-beta.
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Affiliation(s)
- Kenichiro Kashiwagi
- Department of Environmental Medicine and Infectious Diseases, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
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28
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Gramantieri L, Trerè D, Chieco P, Lacchini M, Giovannini C, Piscaglia F, Cavallari A, Bolondi L. In human hepatocellular carcinoma in cirrhosis proliferating cell nuclear antigen (PCNA) is involved in cell proliferation and cooperates with P21 in DNA repair. J Hepatol 2003; 39:997-1003. [PMID: 14642618 DOI: 10.1016/s0168-8278(03)00458-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Proliferating cell nuclear antigen (PCNA) is a nuclear protein involved in DNA-synthesis and repair. During DNA-synthesis and repair the only active PCNA fraction is tightly bound to DNA. Similarly, during DNA-repair, a fraction of p21 colocalizes with PCNA in a detergent-insoluble form. AIM The aim of the study was to analyze to what extent the presence of DNA-bound PCNA and p21 correlates with cell proliferation and DNA-repair in hepatocellular carcinoma (HCC). METHODS Twenty-six HCCs and surrounding cirrhosis were studied. The DNA-bound and detergent-soluble fractions of PCNA and p21 were analyzed by immunoblotting. P53 and Ki67-Labeling Index (Ki67-LI) were evaluated by immunocytochemistry. RESULTS Soluble fractions of PCNA and p21 were found in all samples. One out of 26 cirrhotic samples displayed a DNA-bound fraction of PCNA while no case expressed DNA-bound p21. Fourteen HCCs showed a DNA-bound PCNA fraction. A highly significant correlation was found between Ki67-LI and DNA-bound PCNA but not with detergent-soluble PCNA. DNA-bound p21 and PCNA, indicating ongoing DNA repair activity, were present in 6 of these 14 HCCs and correlated with a high histological grade and high Ki67-LI. CONCLUSIONS Our results suggest that in HCC PCNA participates both in DNA synthesis and repair and that highly proliferating HCCs may display a sustained DNA-repair.
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Affiliation(s)
- Laura Gramantieri
- Center for Applied Biomedical Research (CRBA), University of Bologna and St. Orsola-Malpighi University Hospital, Bologna, Italy
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Trerè D, Borzio M, Morabito A, Borzio F, Roncalli M, Derenzini M. Nucleolar hypertrophy correlates with hepatocellular carcinoma development in cirrhosis due to HBV infection. Hepatology 2003; 37:72-8. [PMID: 12500191 DOI: 10.1053/jhep.2003.50039] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Patients with cirrhosis are at significant risk for hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the relationship between the percentage of hepatocytes showing nucleolar hypertrophy and the development of HCC in cirrhosis of different causes. A total of 111 cirrhotic patients were studied, with a mean follow-up period of 83.3 months. Histologic sections from liver biopsy specimens were silver stained for selective visualization of the nucleolus; the nucleolar area was measured by image cytometry. Nucleoli with a size of 7 microm(2) or greater were considered to be hypertrophic. The nucleolar index was obtained by calculating the percentage of hepatocytes disclosing a nucleolar area of 7 microm(2) or greater. During the observation time, HCC was diagnosed in 39 of 111 patients. The incidence rate of HCC was greater in patients with nucleolar indexes of 2.5 or greater than in patients with nucleolar indexes of less than 2.5 (16.49%/y vs. 3.41%/y, respectively; P <.0001). The capacity of the nucleolar index to predict HCC development was separately tested in groups of patients divided by etiology, and it was found to be particularly relevant in hepatitis B virus (HBV)-related cirrhosis (P =.0006). Among patients with hepatitis C virus (HCV) infection, high nucleolar-index values were associated with a greater risk for HCC development, but the difference in the incidence rate of HCC between groups with a nucleolar index of 2.5 or greater and less than 2.5 was not statistically significant (P =.0944). In conclusion, our results have shown that high percentages of hepatocytes showing nucleolar hypertrophy significantly predict HCC development in patients with HBV infection, whereas their predictive value in HCV-related cirrhosis seems to be lower.
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Affiliation(s)
- Davide Trerè
- Department of Experimental Pathology, Unit of Clinical Pathology, University of Bologna, Italy.
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Morinaga S, Yamamoto Y, Noguchi Y, Imada T, Rino Y, Akaike M, Sugimasa Y, Takemiya S, Kameda Y, Takanashi Y. Cyclooxygenase-2 mRNA is up-regulated in cirrhotic or chronic hepatitis liver adjacent to hepatocellular carcinoma. J Gastroenterol Hepatol 2002; 17:1110-6. [PMID: 12201873 DOI: 10.1046/j.1440-1746.2002.02836.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is unique in that its carcinogenesis is related to inflammatory changes and regenerative activities in the background liver. Although there are some data on cyclooxygenase (COX)-2 expression in HCC by immunohistochemical studies, little is known about the possible role of COX-2 in inducing hepatitis and/or carcinoma. To elucidate whether COX-2 is involved in a part of these processes, we attempted to examine COX-2 mRNA both in the adjacent non-tumoral liver and in HCC. METHODS Twenty-two matched sets of adjacent liver and HCC specimens were analyzed for COX-2 mRNA expression using a real-time quantitative reverse transcription polymerase chain reaction. Cyclooxygenase-2 protein expression was also determined by immunohistochemistry. RESULTS Cyclooxygenase-2 mRNA expression was significantly higher in the adjacent liver than in HCC (P = 0.016). Cyclooxygenase-2 mRNA expression in adjacent liver tissues was positively correlated with the modified histological activity index scores (r = 0.575, P = 0.006), the serum alanine aminotransferase levels (r = 0.536, P = 0.010), and the Ki-67 labeling indices (r = 0.698, P = 0.001). In contrast, COX-2 mRNA expression in HCC was not correlated with any of the clinicopathological features. CONCLUSIONS Cyclooxygenase-2 is expressed at higher levels in the adjacent liver than in HCC, and it may be associated with high levels of necroinflammation and regeneration in the background liver. Conversely, COX-2 may have a lesser role in the progression of HCC.
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Affiliation(s)
- Soichiro Morinaga
- Department of Surgery, Yokohama City Kowan Hospital, Yokohama, Japan.
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31
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Borzio M. Clinical relevance of hepatocyte proliferative activity. Dig Liver Dis 2002; 34:174-6. [PMID: 11990388 DOI: 10.1016/s1590-8658(02)80189-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- M Borzio
- Department of Internal Medicine, Milano, Italy.
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32
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Donato MF, Arosio E, Monti V, Fasani P, Prati D, Sangiovanni A, Ronchi G, Colombo M. Proliferating cell nuclear antigen assessed by a computer-assisted image analysis system in patients with chronic viral hepatitis and cirrhosis. Dig Liver Dis 2002; 34:197-203. [PMID: 11990392 DOI: 10.1016/s1590-8658(02)80193-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Assessment of liver cell proliferation by immunodetection of proliferating cell nuclear antigen may predict regenerative potential and survival of liver and hepatocellular carcinoma risk in patients with chronic viral hepatitis. AIM To evaluate proliferating cell nuclear antigen status and its clinical significance in a large cohort of patients with chronic viral hepatitis and different degree of liver damage by a computer assisted imaging analysis system. MATERIALS Liver biopsies from 358 patients with chronic hepatitis (259 males, 49 years, 63% with hepatitis C infection, 27% with hepatitis B virus, 10% with multiple infections) were studied. METHODS Proliferating cell nuclear antigen was localised by immunoperoxidase on microwave oven pre-treated formalin-fixed, paraffin embedded sections using PC10 monoclonal antibody. Proliferating cell nuclear antigen labelling index was calculated by an automated imaging system (Immagini e Computers, Milan, Italy). RESULTS Mean proliferating cell nuclear antigen labelling index ranged from 0.1% for patients with minimal changes to 3.6% for those with cirrhosis and hepatocellular carcinoma. Overall, proliferating cell nuclear antigen labelling index was higher in males, in older patients, in multiple infections and in hepatitis C virus compared to hepatitis B virus related cases. By linear regression analysis, proliferating cell nuclear antigen labelling index correlated with older age, male gender; higher transaminase levels, hepatitis C virus, higher histological gradIng and staging: by multivariate analysis male gender, hepatitis C virus, higher grading and staging resulted as independent variables. Both hepatitis C virus or hepatitis B virus cirrhotics had similar liver cell proliferation rate but those with hepatitis B virus had higher prevalence of liver cell dysplasia with respect to those with hepatitis C virus. CONCLUSIONS Proliferating cell nuclear antigen labelling index was a reliable assay for assessing liver cell proliferation rate in patients with chronic viral hepatitis and correlated with liver disease severity
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Affiliation(s)
- M F Donato
- A.M. & A. Migliavacca Liver Center & Italian Foundation for Research on Cancer, Unit of Liver Cancer, IRCCS Maggiore Hospital, University of Milan, Italy.
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Kaneko S, Kobayashi K. Molecular biology of hepatitis C virus in hepatocellular carcinoma. PERSPECTIVES IN MEDICAL VIROLOGY 2002:93-100. [DOI: 10.1016/s0168-7069(02)06068-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Bruix J, Sala M, Llovet JM. Interferon for the prevention of hepatocellular carcinoma. PERSPECTIVES IN MEDICAL VIROLOGY 2002:151-159. [DOI: 10.1016/s0168-7069(02)06073-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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35
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Sangiovanni A, Colombo E, Radaelli F, Bortoli A, Bovo G, Casiraghi MA, Ceriani R, Roffi L, Redaelli A, Rossini A, Spinzi G, Minoli G. Hepatocyte proliferation and risk of hepatocellular carcinoma in cirrhotic patients. Am J Gastroenterol 2001; 96:1575-80. [PMID: 11374702 DOI: 10.1111/j.1572-0241.2001.03780.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES High hepatocyte proliferation has been recently proposed as a risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to assess whether hepatocyte proliferation is an independent risk factor for HCC when considered together with clinical and demographic characteristics. METHODS We retrospectively evaluated 97 consecutive patients with a histological diagnosis of cirrhosis and preserved liver function, enrolled in a surveillance program for early diagnosis of HCC. Hepatocyte proliferation was evaluated by flow-cytometric analysis in liver samples collected at the time of histological diagnosis of cirrhosis. All patients were followed with abdominal US and serum alpha-fetoprotein (AFP) assays every 6 months. RESULTS During a mean follow-up of 53 months (range, 12-120 months), 12 patients developed HCC, giving an annual incidence of 2.8%. The mean S-phase fraction was 2.5%+/-1.6 in patients who developed HCC and 0.9%+/-0.6 in those who did not (p < 0.0001). By univariate analysis, S-phase fraction 1.8% or higher and AFP higher than 20 ng/ml were the only two variables significantly correlated with the development of HCC (p < 0.0001, p < 0.0001). Multivariate analysis found that both variables were independently associated with HCC development (p < 0.003 and p < 0.005, respectively), with hazard ratios of 8.0 and 7.3 (confidence intervals, 2.1-31.2 and 1.8-29.2). Among patients with high AFP and/or high S-phase fraction, 11 (39%) developed HCC, compared with only one (1%) with a low S-phase fraction and normal AFP, corresponding to HCC yearly incidences of 9.5% and 0.3% (p < 0.00009). CONCLUSIONS Patients with high S-phase fraction and/or above-normal serum AFP are at higher risk of developing HCC and should be offered a close surveillance program.
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Affiliation(s)
- A Sangiovanni
- Department of Pathology, Valduce Hospital, Como, Italy
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Abstract
Chronic hepatitis C virus (HCV) infection eventually leads to cirrhosis in 20-30% of patients and to hepatocellular carcinoma (HCC) in 1-5% of patients. Rates of sustained virological response with standard interferon-alpha (IFN-alpha) are low in patients without cirrhosis (generally < 20%) and are even lower in those with cirrhosis. Combination therapy with IFN and ribavirin improves response rates in patients with chronic hepatitis C without cirrhosis, and the results from subgroups of HCV-infected patients with advanced fibrosis or cirrhosis are encouraging. Importantly, treatment with IFN slows progression of liver fibrosis, regardless of HCV genotype or early response to therapy, and reduces the risk of HCC by two- to fivefold. The risk of development of HCC is also lower in patients who show at least a partial response to IFN therapy compared with those who show no response. There is a clear need for more definitive studies of treatment in patients with chronic hepatitis C and cirrhosis, ideally using therapies with greater efficacy. Nonetheless, based on the potential to slow the progression of liver fibrosis (regardless of treatment response) and to reduce the risk of HCC, a greater number of HCV-infected patients with cirrhosis should be considered as candidates for IFN treatment. Preliminary data indicate that pegylated IFNs have improved virological response rates and may have additional clinical benefits in the prevention or reduction of fibrosis and retardation of progression of cirrhosis and HCC in these patients.
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Affiliation(s)
- S Zeuzem
- Medizinische Klinik II, Zentrum der Inneren Medizin, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt a.M., Germany
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Attallah AM, Tabll AA, Salem SF, El-Sadany M, Ibrahim TA, Osman S, El-Dosoky IM. DNA ploidy of liver biopsies from patients with liver cirrhosis and hepatocellular carcinoma: a flow cytometric analysis. Cancer Lett 1999; 142:65-9. [PMID: 10424782 DOI: 10.1016/s0304-3835(99)00165-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Flow cytometric DNA analysis was used to assess cellular kinetics of needle liver biopsies from patients with liver cirrhosis and hepatocellular carcinoma (HCC). An abnormal DNA content was shown in 44.5% of liver cirrhosis cases and in 78.6% of tumor sites. The number of proliferating cells (S + G2M%) was significantly increased in cirrhotic liver (P < 0.05). Dysplasia was found in 66% of cirrhotic specimens. All negative dysplasia specimens showed a diploid pattern while 69% of positive dysplastic specimens were aneuploid (P < 0.001). In conclusion, cell proliferation, aneuploidy and liver cell dysplasia are important indicators in liver cirrhosis for the development of HCC.
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Affiliation(s)
- A M Attallah
- Biotechnology Research Center, New Damietta City, Egypt
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38
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Dutta U, Kench J, Byth K, Khan MH, Lin R, Liddle C, Farrell GC. Hepatocellular proliferation and development of hepatocellular carcinoma: a case-control study in chronic hepatitis C. Hum Pathol 1998; 29:1279-84. [PMID: 9824107 DOI: 10.1016/s0046-8177(98)90257-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Patients with hepatitis C have an increased risk of developing hepatocellular carcinoma (HCC). This is related to the stage of chronic liver disease, as characterized histologically by hepatic fibrosis and architectural distortion, but it is unclear whether histological markers can define the risk of developing HCC. We conducted a case-control immunohistochemical study of Ki-67, a marker for hepatocellular proliferation, in livers of 18 patients who had developed HCC more than 2 years after the biopsy specimen had been taken. Using conditional logistic regression analysis, the results were compared with 18 selected controls, who were age-matched patients with hepatitis C of similar histological stage who had not developed HCC. We also examined livers for cellular dysplasia, p53 mutations, and bcl-2 overexpression, and assessed whether the results could be correlated with demographic and disease-related variables, such as gender, region of birth, alcohol consumption, severity of liver disease, HCV genotype, and markers of hepatitis B virus (HBV) infection. Livers from patients who developed HCC were more often positive for Ki-67 (13 of 18 [72%] v 9 of 18 [50%]; P = .06) and tended to have higher mean Ki-67 scores (6 +/- 7.5 v 3 +/- 4.4; P = .10) compared with control cases. In the HCC-predisposed group, three livers showed large cell dysplasia, two were positive for p53 mutations, and two for bcl-2 overexpression. In contrast, in the non-HCC group, only one case had dysplasia, and none were positive for immunostaining for p53 or bcl-2 mutations. With the exception of one case, all livers with large cell dysplasia or p53 mutations and bcl-2 overexpression were also positive for Ki-67. Twelve (55%) of the 22 Ki-67-positive cases were anti-HBc-positive in the serum, in contrast to 2 of 14 (14%) patients in the Ki-67-negative group (P = .01). Patients with evidence of past infection with HBV were more often Ki-67 positive than those who had no evidence of past infection (85% [11 of 13] v 45% [10 of 22]; P = .02). There were no other associations between demographic or disease-related variables and Ki-67 expression. Increased hepatocellular proliferative activity, as assessed by Ki-67 expression, may be one factor indicative of an increased risk of developing HCC among patients with chronic hepatitis C. Furthermore, past infection with HBV appears to be an important correlate of increased hepatocellular proliferation in hepatitis C.
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Affiliation(s)
- U Dutta
- University of Sydney, and Department of Gastroenterology and Hepatology, Westmead Hospital, NSW, Australia
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39
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Bottelli R, Tibballs J, Hochhauser D, Watkinson A, Dick R, Burroughs AK. Ultrasound screening for hepatocellular carcinoma (HCC) in cirrhosis: the evidence for an established clinical practice. Clin Radiol 1998; 53:713-6. [PMID: 9817086 DOI: 10.1016/s0009-9260(98)80311-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Improvement in our current knowledge of epidemiology, natural history and treatment modalities form the background to generalize the use of ultrasound screening in cirrhosis. The cumulative probability of developing cancer is extremely high in cirrhotics and allows to focus screening programs on a well defined risk group thus maximizing cost-effectiveness. This review article highlights scientific evidences in favour of a generalized practice of US screening.
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Affiliation(s)
- R Bottelli
- Liver Transplantation and Hepatobiliary Medicine, Royal Free Hospital, London, UK
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40
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Benvegnù L, Chemello L, Noventa F, Fattovich G, Pontisso P, Alberti A. Retrospective analysis of the effect of interferon therapy on the clinical outcome of patients with viral cirrhosis. Cancer 1998; 83:901-9. [PMID: 9731893 DOI: 10.1002/(sici)1097-0142(19980901)83:5<901::aid-cncr15>3.0.co;2-z] [Citation(s) in RCA: 97] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Recent data suggest that interferon therapy (IFN) can reduce the risk of progression to hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related cirrhosis. METHODS A cohort of 189 patients with Child's Stage A cirrhosis of viral etiology followed prospectively were analyzed retrospectively to assess the effects of IFN on the clinical course and development of HCC. RESULTS During a mean follow-up of 71.5+/-23.6 months, 7.9% of 88 treated and 21.8% of 101 untreated patients showed worsening of the Child's disease stage (P < 0.01); 5.6% of treated and 26.7% of untreated patients developed HCC (P < 0.001); and 3.4% of treated and 19.8% of untreated patients died of liver disease or underwent orthotopic liver transplantation (OLT) (P < 0.005). Using Cox's regression analysis, no treatment with IFN, high bilirubin and alkaline phosphatase (ALP) levels, and low leukocyte counts and prothrombin activity (PT) were associated significantly with worsening of Child's disease stage; no treatment with IFN, long term disease, low albumin and PT, and high gamma-glutamyl transpeptidase (GGT) were related significantly to HCC development; and no treatment with IFN, low albumin and PT, and high GGT and ALP were associated significantly with reduced survival. After adjustment for independent risk factors identified by multivariate analysis, the estimated cumulative probability of worsening of cirrhosis (P < 0.05), development of HCC (P < 0.001), and death or OLT (P < 0.005) was significantly lower in IFN-treated patients compared with untreated patients. This beneficial effect of therapy was statistically evident only in HCV positive patients. CONCLUSIONS These results support the hypothesis that IFN improves clinical outcomes and reduces progression to HCC in patients with HCV-related cirrhosis. These conclusions, based on retrospective data, should be confirmed prospective.
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Affiliation(s)
- L Benvegnù
- Department of Clinical and Experimental Medicine, University of Padova, Italy
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41
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Chenoufi N, Drénou B, Loréal O, Pigeon C, Brissot P, Lescoat G. Antiproliferative effect of deferiprone on the Hep G2 cell line. Biochem Pharmacol 1998; 56:431-7. [PMID: 9763218 DOI: 10.1016/s0006-2952(98)00071-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Iron is an essential element in cellular metabolism and the growth of all living species, and is involved in DNA replication. The risk of hepatocellular carcinoma development is associated with an increase in iron availability. The aim of the present work was to investigate the effect of an oral iron chelator, deferiprone (CP20), on HepG2 cell-line proliferation in culture. HepG2 cell cultures were maintained in the absence of fetal calf serum (FCS) and in the presence or not (control cultures) of CP20 at the concentrations of 50 or 100 microM; deferoxamine (DFO) was used as an iron chelator reference. Cell proliferation was investigated by the analysis of DNA synthesis using [3H] methyl-thymidine incorporation and of the cell cycle by flow cytometry. Iron chelation efficiency in the culture model was studied by analyzing the effect of CP20 on radioactive iron uptake, intracellular ferritin level, and transferrin receptor expression. CP20, at the concentration of 50 or 100 microM, inhibited DNA synthesis after 48 hr of incubation and induced an accumulation of the cells in the S phase of the cell cycle. Iron chelators inhibited cellular iron uptake, decreased intracellular ferritin level, and increased transferrin receptor protein and mRNA levels. Our results show that CP20 as well as deferoxamine inhibit HepG2 cell proliferation and block cell cycle in the S phase.
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Affiliation(s)
- N Chenoufi
- Liver Research Unit, INSERM U49, Pontchaillou University Hospital, Rennes, France
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42
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Borzio M, Trerè D, Borzio F, Ferrari AR, Bruno S, Roncalli M, Colloredo G, Leandro G, Oliveri F, Derenzini M. Hepatocyte proliferation rate is a powerful parameter for predicting hepatocellular carcinoma development in liver cirrhosis. Mol Pathol 1998; 51:96-101. [PMID: 9713593 PMCID: PMC395617 DOI: 10.1136/mp.51.2.96] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
AIMS A sound predictive test is lacking for the identification of cirrhotic patients at high risk of developing hepatocellular carcinoma. The present study evaluates the measurement of hepatocyte expression of silver stained nucleolar organiser region (AgNOR) proteins as a risk factor for the development of hepatocellular carcinoma in cirrhosis. METHODS Liver biopsies from 176 cirrhotic patients included in a follow up surveillance programme for hepatocellular carcinoma development were evaluated prospectively for hepatocyte AgNOR protein quantity. The follow up programme consisted of clinical and biochemical assessment every three months, and ultrasound scanning and serum alpha-fetoprotein (alpha FP) assessment every six months. Histological sections from the needle biopsies performed at enrollment were stained selectively for AgNOR proteins and the percentage of hepatocytes with an AgNOR protein area > or = 7 micron 2, indicative of a proliferative state (AgNOR proliferation index (AgNOR-PI)), was measured. RESULTS During the mean (SD) follow up time of 65.5 (36.29) months (range, 12-143; median, 67), hepatocellular carcinoma was diagnosed in 48 of 176 patients (27.3%). The AgNOR-PI of the whole series ranged from 0% to 5% (median, 0.9%), and was significantly higher in patients with liver cell dysplasia and hepatitis B surface antigen (HBsAg) positivity (p < 0.0001 and p = 0.0002, respectively). The 176 patients were divided into two groups according to their AgNOR-PI scores; a cut off value of 2.5% defined by the receiver operating characteristic curve and the Youden index was used. Forty two patients were included in the high AgNOR-PI (< 2.5%) group, and 134 patients the low AgNOR-PI (< 2.5%) group. In the high AgNOR-PI group, 25 of 42 patients developed hepatocellular carcinoma, in contrast to only 23 of 134 patients (17.2%) in the group with a low AgNOR-PI (p < 0.0001). Hepatocellular carcinoma development was also significantly more frequent in patients with liver cell dysplasia and HBsAg positivity. Multivariate analysis using AgNOR-PI, liver cell dysplasia, HBsAg positivity, and hepatitis C virus (HCV) infection as covariates demonstrated that the AgNOR-PI parameter was the only significant predictor of hepatocellular carcinoma development. CONCLUSIONS These results demonstrate that a high hepatocyte proliferation rate is a major risk factor for hepatocellular carcinoma development in the cirrhotic liver. Therefore, the evaluation of the hepatocyte proliferation rate is very important to identify patients requiring a more strict follow up programme for early diagnosis of hepatocellular carcinoma.
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Affiliation(s)
- M Borzio
- First Department of Medicine, Fatebenefratelli Hospital, Milan, Italy
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Stål P, Olsson J, Svoboda P, Hultcrantz R, Harms-Ringdahl M, Eriksson LC. Studies on genotoxic effects of iron overload and alcohol in an animal model of hepatocarcinogenesis. J Hepatol 1997; 27:562-71. [PMID: 9314135 DOI: 10.1016/s0168-8278(97)80362-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS In order to examine whether iron and alcohol act synergistically during tumor initiation in vivo, we investigated the effects of dietary iron overload and a liquid ethanol-containing diet on the initiation phase of the Solt & Farber model of chemical hepatocarcinogenesis. METHODS Following dietary supplementation with carbonyl iron for 8 weeks and ethanol pair-feeding according to Lieber deCarli for 5 weeks, animals were subjected to partial hepatectomy in order to induce regenerative cell proliferation and thereby "fix" putative DNA lesions. Levels of malondialdehyde, reduced and oxidized ubiquinone-9, alpha-tocopherol and 8-oxo-2'-deoxyguanosine were analyzed in liver tissue removed at the time of partial hepatectomy, and blood was collected for determination of alanine amino-transferase activities. Following a 2-week recovery period, promotion was achieved with 0.02% dietary 2-acetylaminofluorene and carbon tetrachloride. Two weeks after the completion of promotion, animals were sacrificed and the number of preneoplastic, glutathione S-transferase 7,7-positive lesions counted. Animals initiated with diethylnitrosamine served as a positive control group. RESULTS Serum aminotransferase activities were significantly increased, and hepatic contents of ubiquinol-9 (reduced ubiquinone-9) were significantly decreased in animals exposed to the combination of iron and ethanol in comparison to the other groups. Livers from iron-treated animals had decreased levels of alpha-tocopherol and increased contents of malondialdehyde, whereas treatment with ethanol did not further enhance these alterations. Levels of 8-oxo-2'-deoxyguanosine were not significantly different in animals treated with iron, ethanol or iron + ethanol as compared with controls. The number of preneoplastic foci at the time of sacrifice was not increased in livers exposed to iron and/or ethanol as compared with those from control animals. As expected, the number of foci was significantly increased in positive controls which were initiated with diethylnitrosamine. CONCLUSIONS Iron potentiated the cytotoxic effects of ethanol, resulting in increased serum aminotransferase activities and decreased hepatic contents of ubiquinol. However, the combination of iron and ethanol did not exert genotoxic effects detectable as enhanced hepatic levels of 8-oxo-2'-deoxyguanosine, or increased formation of preneoplastic, glutathione S-transferase 7,7-positive lesions in the Solt & Farber model of chemical hepatocarcinogenesis.
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Affiliation(s)
- P Stål
- Department of Gastroenterology and Hepatology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden
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Mansouri A, Fromenty B, Berson A, Robin MA, Grimbert S, Beaugrand M, Erlinger S, Pessayre D. Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients. J Hepatol 1997; 27:96-102. [PMID: 9252080 DOI: 10.1016/s0168-8278(97)80286-3] [Citation(s) in RCA: 113] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS A 4977-base pair deletion has been detected in the hepatic mitochondrial DNA of alcoholic patients with microvesicular steatosis, a lesion ascribed to impaired mitochondrial beta-oxidation. However, only a single deletion had been looked for in this previous study, and it could not be determined whether the deletion was preexisting or acquired. Alcohol abuse increases the formation of reactive oxygen species in hepatic mitochondria. If this effect accelerates the oxidative aging of mitochondrial DNA, several other mutations would be expected. METHODS The mtDNA region extending from nucleotide 8167 to nucleotide 14246 was screened for the presence of large mitochondrial DNA deletions in 58 alcoholic patients and 67 age-matched non-alcoholic controls. Hepatic DNA was subjected to polymerase chain reactions that amplified non-deleted and deleted mitochondrial DNA, respectively, and the boundaries of the mitochondrial DNA deletions were sequenced. RESULTS Only 3% of the non-alcoholic controls carried a mitochondrial DNA deletion, whereas 24% of all alcoholic patients and 85% of the 13 alcoholic patients with microvesicular steatosis exhibited either single or multiple 4977, 5385, 5039 and 5556-base pair mitochondrial DNA deletions. No deletion(s) were observed, however, in 13 patients with microvesicular steatosis due to other causes. CONCLUSIONS Diverse mitochondrial DNA rearrangements are observed in alcoholic patients with microvesicular steatosis. We suggest that alcohol abuse leads to premature oxidative aging of mitochondrial DNA. Hypothetically, oxidative damage to mitochondrial constituents (DNA, proteins and lipids) may favor microvesicular fat deposition.
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Affiliation(s)
- A Mansouri
- INSERM Unité 24 and Centre de Recherche de Physiopathologie Hépatique(Association Claude Bernard), Hôpital Beaujon, Clichy, France
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Sathar SA, Sarkar C, Nayak NC. Hepatocyctic proliferation in chronic liver disease: A study of liver biopsies using immunohistochemical localization of proliferating cell nuclear antigen. Ann Saudi Med 1997; 17:363-7. [PMID: 17369744 DOI: 10.5144/0256-4947.1997.363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- S A Sathar
- Department of Pathology, Faculty of Medicine, Kuwait, University, Kuwait
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Ruà S, Comino A, Fruttero A, Torchio P, Bouzari H, Taraglio S, Torchio B, Capussotti L. Flow cytometric DNA analysis of cirrhotic liver cells in patients with hepatocellular carcinoma can provide a new prognostic factor. Cancer 1996; 78:1195-202. [PMID: 8826940 DOI: 10.1002/(sici)1097-0142(19960915)78:6<1195::aid-cncr5>3.0.co;2-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND DNA flow cytometry of hepatocellular carcinoma (HCC) cells has been investigated in many studies, but, to the best of our knowledge, there are no data on DNA analysis of cirrhotic parenchyma around the HCC. In this study, cell kinetics and ploidy of parenchymal cells around HCC were performed to ascertain if this would predict the possibility of recurrence in the cirrhotic areas. METHODS The DNA content of 93 cases of HCC and of cirrhotic liver around the tumor nodules was analyzed by flow cytometry. Ploidy and proliferative index of HCC and cirrhotic liver were compared with macroscopic, histologic, and clinical features of each case and linked with the behavior of these tumors. Survival curves were assessed according to the Kaplan-Meier method. A multivariate analysis based on Cox proportional hazards regression model was performed on cases of diploid cirrhosis cells in which the S-phase fraction was evaluable. RESULTS The univariate analysis of survival suggested significant roles for age, number of intrahepatic nodules, Edmondson-Steiner's classification, portal invasion, vascular invasion, presence of necrosis, hepatitis B surface antigen, alpha-feto-protein, Child's score, ploidy, and S-phase fraction of HCC cells. The DNA analysis of the cirrhotic cells showed that polyploidy was dramatically reduced in patients with HCC, compared with normal hepatocytes, and aneuploid clones were present among diploid cells. High S-phase fraction of cirrhotic cells and Child-Pugh classification were the strongest independent parameters affecting the tumor behavior in this study. CONCLUSIONS The results of this study suggest that S-phase fraction of cirrhotic liver parenchyma may be employed as a new parameter in the prognostic evaluation of HCC patients.
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Affiliation(s)
- S Ruà
- Department of Pathological Anatomy and Histology, City Hospital, Cuneo, Italy
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47
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Paterlini P, Flejou JF, De Mitri MS, Pisi E, Franco D, Bréchot C. Structure and expression of the cyclin A gene in human primary liver cancer. Correlation with flow cytometric parameters. J Hepatol 1995; 23:47-52. [PMID: 8530809 DOI: 10.1016/0168-8278(95)80310-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND/AIMS The cyclin A gene plays an important role in both the S and G2-M phases of the cell cycle, and has been identified at a site of hepatitis B virus DNA integration in a human liver cancer. We analyzed tumorous and non-tumorous samples from patients with primary liver cancer to determine whether a) the cyclin A gene is rearranged in liver tumors and b) the cyclin A transcript level correlates with the percentage of proliferating cells. METHODS Samples from 43 patients were analyzed by Southern blot. Cyclin A RNA accumulation was evaluated in 18 cases by slot blot and correlated with the percentage of cells in S plus G2-M phases defined by flow cytometry. RESULTS No rearrangement of the cyclin A gene was found in tumorous compared to non-tumorous tissue. A very strong positive correlation was found between the cyclin A RNA level and the cumulative percentage of cells in S plus G2-M phases (r = 0.99; p < 0.0001). CONCLUSIONS This in vivo study shows that the expression of cyclin A RNA correlates with the percentage of proliferating cells in primary liver cancer. Thus, cyclin A is a new potential liver tumor cell proliferation index.
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48
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Stál P, Hultcrantz R, Möller L, Eriksson LC. The effects of dietary iron on initiation and promotion in chemical hepatocarcinogenesis. Hepatology 1995; 21:521-8. [PMID: 7843726 DOI: 10.1002/hep.1840210237] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The aim of this study was to evaluate the effects of dietary iron on hepatocarcinogenesis in an animal model mimicking noncirrhotic genetic hemochromatosis. Iron overload may lead to liver cirrhosis and an increased risk of developing primary hepatocellular carcinoma. It is unknown if iron is of pathogenic importance for the carcinogenic process, or whether the increased cancer risk results solely from the cirrhotic process. We investigated the initiating, promoting, and mitogenic properties of carbonyl iron in the Solt-Farber model of chemical hepatocarcinogenesis. A diet supplemented with 2.5% to 3.0% carbonyl iron was either added to, or replaced, the initiating and promoting events in the model. None of the animals developed hepatic fibrosis. Hepatic iron was increased 6- to 13-fold in iron-treated animals, and predominantly located in periportal hepatocytes. Iron as an initiator did not increase the number of glutathione-S-transferase-Yp-positive foci. Iron reduced the number of foci when added to low-dose diethylnitrosamine plus partial hepatectomy, which may be explained by a delayed hepatic regeneration in iron-loaded liver. As a promoter, iron did not selectively induce proliferation of initiated cells. Added to a complete promotive regimen, iron decreased the volume density of preneoplastic nodules, possibly because of a mitostimulatory effect of iron on normal hepatocytes surrounding the nodules. Iron increased the hepatocyte labeling index and counteracted the mitoinhibitory effect of 2-acetylaminofluorene on regenerating liver.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- P Stál
- Division of Gastroenterology and Hepatology, Karolinska Institutet, Huddinge University Hospital, Sweden
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49
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Fromenty B, Grimbert S, Mansouri A, Beaugrand M, Erlinger S, Rötig A, Pessayre D. Hepatic mitochondrial DNA deletion in alcoholics: association with microvesicular steatosis. Gastroenterology 1995; 108:193-200. [PMID: 7806041 DOI: 10.1016/0016-5085(95)90024-1] [Citation(s) in RCA: 111] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND/AIMS Alcohol abuse may lead to microvesicular steatosis, a lesion ascribed to impaired mitochondrial function. Because alcohol abuse leads to reactive oxygen species in the hepatic mitochondria, it may damage mitochondrial DNA. The aim of this study was to look for the presence of the "common" 4977-base pair deletion in the hepatic mitochondrial DNA of alcoholic patients and age-matched, nonalcoholic controls. METHODS Hepatic DNA was subjected to two polymerase chain reactions that amplified non-deleted and deleted mitochondrial DNA, respectively. RESULTS The deletion was found in 6 of 10 alcoholics with microvesicular steatosis, 2 of 17 alcoholic patients with macrovacuolar steatosis, but in none of 12 patients with acute alcoholic hepatitis, 11 patients with alcoholic cirrhosis, or 62 nonalcoholic patients of comparable ages with various other liver diseases or normal liver histology. In all patients with the deletion, restriction fragments of deleted mitochondrial DNA co-migrated with those of reference Pearson bone marrow-pancreas syndrome patients with the common mitochondrial DNA deletion. CONCLUSIONS The common deletion is frequent in the hepatic DNA of alcoholic patients with microvesicular steatosis. Alcohol-induced mitochondrial DNA damage may contribute to the occurrence of this lesion in some alcoholics.
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Affiliation(s)
- B Fromenty
- INSERM Unité 24, Hôpital Beaujon, Clichy, France
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