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Heiat M, Javanbakht M, Jafari D, Poudineh M, Heydari F, Sharafi H, Alavian SM. Correlation of IL-10 and IL18 with the development of liver cirrhosis associated with hepatitis B virus infection: A systematic review. Cytokine 2025; 186:156818. [PMID: 39671883 DOI: 10.1016/j.cyto.2024.156818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/02/2024] [Accepted: 11/16/2024] [Indexed: 12/15/2024]
Abstract
BACKGROUND Patients who have been infected with the Hepatitis B virus (HBV) are susceptible to developing liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The objective of this systematic review was to comprehensively scrutinize the existing evidence concerning the association between host genetic polymorphisms and HBV-associated LC. METHODS We searched databases of PubMed, Scopus, and Web of Science for relevant articles published from building databases to 25 October 2023. RESULT We detected 104 relevant articles, relating to 84 individuals genes. Nine genes had the strong evidence of correlation, including IL-10, IL-18, IL-1B, TGF- β, TLR3, STAT4, IL-1RN, Tim3, and IFN receptors. A positive correlation was found for 33 genes but this data had not yet been replicated, 11 genes had limited or mixed evidence of a correlation, and 34 genes indicated no correlation. IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. CONCLUSION IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. It is of necessary to take into account the fundamental mechanism behind these associations and discern those that are confounded by the coexistence of other LC/HCC risk factors and response to therapy. These results are expected to guide future studies on the genetic susceptibility of HBV-related LC/HCC.
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Affiliation(s)
- Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mohammad Javanbakht
- Nephrology and Urology Research Center, Clinical Science Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Davood Jafari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Fatemeh Heydari
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Chen G, Hu C, Lai P, Song Y, Xiu M, Zhang H, Zhang Y, Huang P. Association between TGF-β1 rs1982073/rs1800469 polymorphism and lung cancer susceptibility: An updated meta-analysis involving 7698 cases and controls. Medicine (Baltimore) 2019; 98:e18028. [PMID: 31764821 PMCID: PMC6882652 DOI: 10.1097/md.0000000000018028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 10/04/2019] [Accepted: 10/19/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND There have been several case-control studies to assess the relationship between the transforming growth factor-β1 (TGF-β1) T + 869C (rs1982073)/C-509T (rs1800469) gene polymorphism and lung cancer in recent years; however, the results remain controversial. In this study, we investigated the potential correlation between the TGF-β1 T + 869C/C-509T polymorphism and increased risk of lung cancer through meta-analysis. METHODS We searched the Cochrane Library database, Embase, PubMed, Web of Science, China National Knowledge Infrastructure, and the Wanfang Data Information Service platform to identify relevant case-control studies in strict accordance with the inclusion and exclusion criteria. The odds ratio (OR) and its 95% confidence interval (95% CI) were used to evaluate the correlation between TGF-β1 gene polymorphism and lung tumor risk. Sensitivity analysis and Egger test were used to evaluate the stability of the results and possible publication bias. RESULTS A total of 8 studies, with 3680 patients and 4018 controls, were included. The meta-analysis revealed that there was no conspicuous correlation between the TGF-β1 T + 869C (rs1982073)/C-509T (rs1800469) variant and lung cancer in the overall population. For TGF-β1 C-509T, a significant decreased risk was identified in patients with nonsmall-cell lung cancer (NSCLC) in the analysis stratified by disease (TT vs CT + CC: P = .02, OR = 0.49, 95% CI 0.27-0.90). However, for TGF-β1 T + 869C, subgroup analysis showed no correlation between the T + 869C polymorphism and lung cancer susceptibility in patients with NSCLC. In the subgroup analysis by ethnicity, no distinct association was observed between T + 869C (rs1982073)/C-509T (rs1800469) polymorphism and lung cancer susceptibility in the Asian and Caucasian groups. Moreover, no significant association was found in the analysis of groups stratified by age, sex, and smoking history. CONCLUSION The TGF-β1 T + 869C (rs1982073) and C-509T (rs1800469) polymorphisms are not implicated in lung cancer susceptibility in the overall population. However, our analysis indicated that the C-509T (rs1800469) polymorphism decreases the risk of lung cancer in patients with NSCLC.
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Affiliation(s)
- Guangyuan Chen
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi
| | - Cong Hu
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi
| | - Penghui Lai
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi
| | - Yuxuan Song
- Department of Urology, Tianjin Medical University General Hospital, Tianjin
| | - Mengxi Xiu
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi
| | - Haifei Zhang
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi
| | - Yiling Zhang
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi
| | - Peng Huang
- Center for Evidence-based Medicine
- Jiangxi Province Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang, China
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Ghani MU, Haque A, Iqbal MS, Ashfaq UA, Mausood MS, Qasim M, Jahan S, Shamsi FB, Yousaf M. TGF-β1 rs1800469 gene polymorphism in the development of cirrhosis & hepatocellular carcinoma in Pakistani HCV patients. Future Virol 2019. [DOI: 10.2217/fvl-2019-0047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Hepatocellular carcinoma (HCC) has been increasing among Pakistani males. Aim: The main objective of this study was to evaluate the role of TGF-β-1 gene polymorphism as a risk factor in chronic hepatitis C virus (HCV) infected HCC patients in Pakistan. Patients & methods: A total of 286 subjects were recruited into three different groups (Group I: 96 healthy controls, Group II: 96 HCV, Group III: 94 HCC). Results: A significant increase in genotype and allele frequencies of TGF-β-1 gene was observed in HCC, HCV with OR = 1.9; 95% CI: 1.275–2.871; p > 0.05, OR = 1.6; 95% CI: 1.12–2.51; p > 0.05 and OR = 1.7; 95% CI: 1.036–1.923; p > 0.05. Conclusion: A higher frequency of the TT genotype and T allele of the TGF-β-1 gene is observed in Pakistani HCV and HCC patients.
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Affiliation(s)
- Muhammad Usman Ghani
- Department of Bioinformatics & Biotechnology, GC University, Faisalabad, Pakistan
| | - Asma Haque
- Department of Bioinformatics & Biotechnology, GC University, Faisalabad, Pakistan
| | - Muhammad Sarfaraz Iqbal
- Department of Biotechnology, School of Applied Biology(SAB), University of Okara, Okara, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics & Biotechnology, GC University, Faisalabad, Pakistan
| | | | - Muhammad Qasim
- Department of Bioinformatics & Biotechnology, GC University, Faisalabad, Pakistan
| | - Shah Jahan
- Department of Immunology University of Health Science, Lahore, Pakistan
| | - Farwa Batool Shamsi
- Department of Pathology, Faisalabad Medical University, Faisalabad, Pakistan
| | - Muhammad Yousaf
- Department of Pathology, Faisalabad Medical University, Faisalabad, Pakistan
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Lu WQ, Qiu JL, Huang ZL, Liu HY. Enhanced circulating transforming growth factor beta 1 is causally associated with an increased risk of hepatocellular carcinoma: a mendelian randomization meta-analysis. Oncotarget 2018; 7:84695-84704. [PMID: 27835897 PMCID: PMC5356692 DOI: 10.18632/oncotarget.13218] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 10/25/2016] [Indexed: 02/07/2023] Open
Abstract
The aim of this study was to test the causal association between circulating transforming growth factor beta 1 (protein: TGF-β1 and coding gene: TGFB1) and hepatocellular carcinoma by choosing TGFB1 gene C-509T polymorphism as an instrument in a Mendelian randomization (MR) meta-analysis. Ten English articles were identified for analysis. Two authors independently assessed each article and abstracted relevant data. Odds ratio (OR) and weighted mean difference (WMD) with 95% confidence interval (CI) were synthesized under a random-effects model. Overall, the association of C-509T polymorphism with hepatocellular carcinoma was negative, but its association with circulating TGF-β1 was statistically significant, with a higher concentration observed in carriers of the -509TT genotype (WMD, 95% CI, P: 1.72, 0.67–2.78, 0.001) and -509TT/-509TC genotypes (WMD, 95% CI, P: 0.98, 0.43–1.53, < 0.001). In subgroup analysis, C-509T polymorphism was significantly associated with hepatocellular carcinoma in population-based studies under homozygous-genotype (OR, 95% CI, P: 1.74, 1.08–2.80, 0.023) and dominant (OR, 95% CI, P: 1.48, 1.01–2.17, 0.047) models. Further MR analysis indicated that per unit increase in circulating TGF-β1 was significantly associated with a 38% (95% CI: 1.03–4.65) and 49% (95% CI: 1.01–6.06) increased risk of hepatocellular carcinoma under homozygous-genotype and dominant models, respectively. Conclusively, based on a MR meta-analysis, our findings suggest that enhanced circulating TGF-β1 is causally associated with an increased risk of hepatocellular carcinoma.
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Affiliation(s)
- Wei-Qun Lu
- Department of Gastrointestinal Tumor Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ji-Liang Qiu
- Department of Gastrointestinal Tumor Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhi-Liang Huang
- Department of Gastrointestinal Tumor Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Hai-Ying Liu
- Department of Gastrointestinal Tumor Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China
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Transforming growth factor (TGF-β1) gene polymorphisms in Egyptian patients with hepatitis B virus infection. Meta Gene 2017. [DOI: 10.1016/j.mgene.2017.03.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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Eskandari E, Metanat M, Pahlevani E, Nakhzari-Khodakheir T. Association between TGFβ1 polymorphisms and chronic hepatitis B infection in an Iranian population. Rev Soc Bras Med Trop 2017; 50:301-308. [PMID: 28700046 DOI: 10.1590/0037-8682-0266-2016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 03/06/2017] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION: Transforming growth factor-beta 1 (TGFβ1) is a potent suppressive cytokine that contributes to chronic hepatitis B (CHB) infection. Disparities in TGFβ1 production among individuals have been attributed to TGFβ1 genetic polymorphisms. We examined whether three putative polymorphisms in TGFβ1[-509 C/T (rs1800469), +869 C/T (rs1800470), and +11929 C/T (rs1800472)]are associated with CHB infection in a South-Eastern Iranian population. METHODS: In total, 341 subjects were recruited, including 178 patients with CHB and 163 healthy individuals as controls. Genotyping of the three TGFβ1 SNPs was performed by tetra amplification refractory mutation system-PCR. RESULTS: TheTGFβ1 +869 TT vs.CC genotype in codominant (OR=0.445, p=0.012) and TT vs. TC+CC in the recessive (OR=0.439, p=0.003) model as well as the variant allele T vs. C(OR=0.714, p=0.038) were associated with lower CHB infection risk. However, the +11929 C/T polymorphism was associated with increased CHB risk, and the CT vs. CC genotype (OR=2.77, P=0.001) and T variant allele (OR=2.53, P=0.002) were risk factors for CHB. Furthermore, TTT (+869/-509/+11929) and CCC haplotypes were risk and protective factors for CHB, respectively. We found no significant association between viral DNA load and TGFβ1 genotype or hepatic enzyme levels (p >0.05). CONCLUSIONS: Results indicated that the TGFβ1+869TT genotype and T allele were protective factors, whereas the +11929 CT genotype and T allele were risk factors for CHB infection.
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Affiliation(s)
- Ebrahim Eskandari
- Genetic of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.,Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Malihe Metanat
- Infectious Diseases & Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Elham Pahlevani
- Infectious Diseases & Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
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Khaali W, Moumad K, Ben Driss EK, Benider A, Ben Ayoub W, Hamdi-Cherif M, Boualga K, Hassen E, Corbex M, Khyatti M. No association between TGF-β1 polymorphisms and risk of nasopharyngeal carcinoma in a large North African case-control study. BMC MEDICAL GENETICS 2016; 17:72. [PMID: 27733130 PMCID: PMC5062876 DOI: 10.1186/s12881-016-0337-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 10/07/2016] [Indexed: 01/02/2023]
Abstract
Background Genetic susceptibility plays a key role in the development of nasopharyngeal carcinoma (NPC) and in fact the disease presents with an unusually high incidence in certain regions of the world like North Africa. We investigated the association between polymorphism of the Transforming growth factor-β1 (TGF-β1) and risk of NPC in North Africa. TGF-β1 is a multifunctional cytokine that acts as both a tumor suppressor and a stimulator of cancer development; it has been shown to influence risk of numerous other carcinomas including lung, breast and prostate cancer. Methods TGF-β1 polymorphisms C-509T and T869C were studied in a large North African sample of 384 NPC cases and 361 controls, matched for age, sex and urban or rural residence in childhood. Genotypes were determined using polymerase chain reaction–restriction fragment length polymorphism. Results No association was observed between individual single nucleotide polymorphisms or their haplotypes and NPC susceptibility (for TGF-β1 C-509T: OR = 0.74; 95 % CI 0.46 − 1.18; for TGF-β1 T869C: OR = 0.86; 95 % CI 0.56 − 1.31), even when the samples were stratified by age, gender and TNM stage. Conclusion Contrary to what has been observed in Asian samples, in our North African sample, the TGF-β1 C-509T and T869C polymorphisms did not substantially influence NPC susceptibility. Electronic supplementary material The online version of this article (doi:10.1186/s12881-016-0337-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wafa Khaali
- Oncovirology Laboratory, Institut Pasteur du Maroc, 1 Place Louis Pasteur, 20360, Casablanca, Morocco. .,Departement of Biology, Faculty of Sciences, Abdelmalek Essaadi University, 93030, Tetouan, Morocco.
| | - Khalid Moumad
- Oncovirology Laboratory, Institut Pasteur du Maroc, 1 Place Louis Pasteur, 20360, Casablanca, Morocco
| | - El Khalil Ben Driss
- Departement of Biology, Faculty of Sciences, Abdelmalek Essaadi University, 93030, Tetouan, Morocco
| | - Abdellatif Benider
- Service de Radiothérapie, Centre d'oncologie Ibn Rochd, 20360, Casablanca, Morocco
| | - Wided Ben Ayoub
- Association Tunisienne de Lutte Contre le Cancer, 10006, Tunis, Tunisia
| | | | - Kada Boualga
- Service de Radiothérapie Oncologique, Centre Anti-Cancer de Blida, 09000, Blida, Algeria
| | - Elham Hassen
- Molecular Immuno-Oncology Laboratory, Faculty of Medicine, Monastir University, 5019, Monastir, Tunisia
| | - Marilys Corbex
- Who Regional Office for Europe, Marmorvej 51, DK-2100, Copenhagen, Denmark
| | - Meriem Khyatti
- Oncovirology Laboratory, Institut Pasteur du Maroc, 1 Place Louis Pasteur, 20360, Casablanca, Morocco.
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Moudi B, Heidari Z, Mahmoudzadeh-Sagheb H. Impact of host gene polymorphisms on susceptibility to chronic hepatitis B virus infection. INFECTION GENETICS AND EVOLUTION 2016; 44:94-105. [DOI: 10.1016/j.meegid.2016.06.043] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/21/2016] [Accepted: 06/22/2016] [Indexed: 12/15/2022]
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Shi HZ, Ren P, Lu QJ, Niedrgethmnn M, Wu GY. Association between EGF, TGF-β1 and TNF-α gene polymorphisms and hepatocellular carcinoma. Asian Pac J Cancer Prev 2016; 13:6217-20. [PMID: 23464434 DOI: 10.7314/apjcp.2012.13.12.6217] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
INTRODUCTION Up to present, EGF 61*A/G, TGF-β1 -509*T/C and TNF-α -308*A/G gene polymorphisms have been analysed in other cancer entities than hepatocellular carcinoma (HCC). We here investigated the frequency of these gene polymorphisms among HCC patients. MATERIALS AND METHODS A total of 73 HCC patients and 117 cancer-free healthy people were recruited at the Surgical Department of Zhongshan Hospital. Genomic DNA was isolated from peripheral blood and gene polymorphisms were analyzed by PCR-RFLP. RESULTS The distribution of EGF 61*G/G homozygotes among HCC patients was more frequent than that in the control group (24.7% vs 11.1%, OR=2.618, 95%CI=1.195-5.738). In parallel, the frequency of the "G" allele in the HCC patient group was also higher than that in the control group (45.9% vs 33.3%, OR= 1.696, 95%CI=1.110-2.592). No difference could be found for the TGF-β1-509 and TNF-α -308 genotypes. CONCLUSION EGF 61*G/G genotype and G allele are significantly increased among patients with HCC. TGF-β1-509*T/C and TNF-α -308*A/G gene polymorphisms are not related to this cancer entity.
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Affiliation(s)
- Hai-Zhou Shi
- Department of General Surgery, Binzhou Central Hospital, Binzhou Medical College, Bin Zhou, China
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Mathew S, Abdel-Hafiz H, Raza A, Fatima K, Qadri I. Host nucleotide polymorphism in hepatitis B virus-associated hepatocellular carcinoma. World J Hepatol 2016; 8:485-498. [PMID: 27057306 PMCID: PMC4820640 DOI: 10.4254/wjh.v8.i10.485] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Revised: 12/04/2015] [Accepted: 03/07/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is etiologically linked with hepatitis B virus (HBV) and is the leading cause of death amongst 80% of HBV patients. Among HBV affected patients, genetic factors are also involved in modifying the risk factors of HCC. However, the genetic factors that regulate progression to HCC still remain to be determined. In this review, we discuss several single nucleotide polymorphisms (SNPs) which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection such as cyclooxygenase (COX)-2 expression specifically at COX-2 -1195G/A in Chinese, Turkish and Egyptian populations, tumor necrosis factor α and the three most commonly studied SNPs: PAT-/+, Lys939Gln (A33512C, rs2228001) and Ala499Val (C21151T, rs2228000). In genome-wide association studies, strong associations have also been found at loci 1p36.22, 11q22.3, 6p21 (rs1419881, rs3997872, rs7453920 and rs7768538), 8p12 (rs2275959 and rs37821974) and 22q11.21. The genes implicated in these studies include HLA-DQB2, HLA-DQA1, TCF19, HLA-C, UBE2L3, LTL, FDX1, MICA, UBE4B and PG. The SNPs found to be associated with the above-mentioned genes still require validation in association studies in order to be considered good prognostic candidates for HCC. Screening of these polymorphisms is very beneficial in clinical experiments to stratify the higher or lower risk for HCC and may help in designing effective and efficient HCC surveillance programs for chronic HBV-infected patients if further genetic vulnerabilities are detected.
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Affiliation(s)
- Shilu Mathew
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Hany Abdel-Hafiz
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Abbas Raza
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Kaneez Fatima
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Ishtiaq Qadri
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
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Saxena R, Kaur J. Th1/Th2 cytokines and their genotypes as predictors of hepatitis B virus related hepatocellular carcinoma. World J Hepatol 2015; 7:1572-1580. [PMID: 26085916 PMCID: PMC4462695 DOI: 10.4254/wjh.v7.i11.1572] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 01/30/2015] [Accepted: 03/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant type of primary liver cancer, is one of the most serious life-threatening malignancies, worldwide. In majority of the cases, HCC develops after prolonged and persistent chronic liver disease. hepatitis B virus (HBV) or HCV infection is prominent etiological factors, attributing to this condition. It has been well documented that HBV, being the inducer of chronic inflammation, is the main causative agent in causing HCC, particularly in Asian countries. The HBV infection leads to a wide range of clinical symptoms from carrier state to malignancy. Cytokines being immune-modulatory molecules, are the key mediators in the defense mechanism against viral infection. In this regard, this review will detail the substantial role of key Th1: interleukin 1 (IL-1), IL-2, IL-12, tumor necrosis factor-α, interferon-γ; Th2: IL-4, IL-10 and non Th1/Th2: IL-6, transforming growth factor-β1 cytokines genotypes in analyzing the variability in the clinical manifestations in an HBV-afflicted individual, which might finally, culminates into HCC. Since cytokine production is regulated genetically, the cytokine promoter region single-nucleotide polymorphisms induced changes, greatly affects the cytokine production, thus resulting into differential outcome of immune balance.
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Affiliation(s)
- Roli Saxena
- Roli Saxena, Jyotdeep Kaur, Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Jyotdeep Kaur
- Roli Saxena, Jyotdeep Kaur, Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
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Tunçbilek S. Relationship between cytokine gene polymorphisms and chronic hepatitis B virus infection. World J Gastroenterol 2014; 20:6226-6235. [PMID: 24876743 PMCID: PMC4033460 DOI: 10.3748/wjg.v20.i20.6226] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 12/09/2013] [Accepted: 01/02/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is still a public health problem worldwide, being endemic in some parts of the world. It can lead to serious liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular cancer. The differences in host immune response can be one of the reasons for the various clinical presentations of HBV infection. Polymorphisms of genes encoding the proinflammatory and antiinflammatory cytokines, which are responsible for regulation of the immune response, can affect the clinical presentation of the infection. Particularly, the polymorphisms of the genes encoding cytokines such as interleukin (IL)-1, IL-6, IL-8, IL-10, IL-18, IL-28B, interferon-γ, tumor necrosis factor-α, tumor growth factor-β1, and regulatory molecules like vitamin D receptor and chemokine receptor 5 can be responsible for different clinical presentations of HBV infections. The genomic information about cytokines and other mediators can be important for determining high-risk people for developing chronic hepatitis or hepatocellular cancer and may be used to plan treatment and preventive approaches for these people. In this review, the current knowledge in the literature on the association between cytokine/regulatory molecule gene polymorphisms and clinical course of chronic HBV infection is summarized, and the clinical implementations and future prospects regarding this knowledge are discussed.
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Wang E, Wang Z, Liu S, Gu H, Gong D, Hua K, Nie Y, Wang J, Wang H, Gong J, Zhang Y, Zhang H, Liu R, Hu S, Zhang H. Polymorphisms of VEGF, TGFβ1, TGFβR2 and conotruncal heart defects in a Chinese population. Mol Biol Rep 2014; 41:1763-1770. [PMID: 24443223 DOI: 10.1007/s11033-014-3025-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 01/03/2014] [Indexed: 02/01/2023]
Abstract
Genetic variants may determine susceptibility of congenital heart disease (CHD). To evaluate the impact of transforming growth factor-β1 (TGFβ1), TGFβ receptor II (TGFβR2) and vascular endothelial growth factor (VEGF) polymorphisms on conotruncal heart defects susceptibility, we genotyped six functional polymorphisms TGFβ1 rs1800469 C>T, TGFβR2 rs3087465 G>A, VEGF -2578C>A, -1498T>C, -634G>C and +936C>T in a hospital based case-control study of 244 conotruncal heart defects cases and 136 non-CHD controls in a Chinese population. Logistic regression analyses revealed that if the TGFβ1 rs1800469 CC homozygote genotype was used as the reference group, subjects carrying the CT variant heterozygote had a significant 0.48-fold decreased risk of conotruncal heart defects [odds ratio (OR) = 0.52; 95% confidence interval (CI) = 0.30-0.88], subjects carrying the TT variant homozygote had a significant 0.47-fold decreased risk of conotruncal heart defects (OR 0.53; 95% CI 0.28-1.00). In stratification analyses, the TGFβ1 rs1800469 C>T genotype was associated with a decreased risk for tetralogy of fallot in homozygote comparisons (OR 0.47; 95% CI 0.22-0.99), a decreased risk for transposition of great artery in the dominant genetic model (OR 0.49; 95 % CI 0.28-0.87) and heterozygote comparisons (OR 0.45; 95% CI 0.24-0.83). Our findings suggest that TGFβ1 rs1800469 C>T polymorphism was significantly associated with decreased risk of conotruncal heart defects. TGFβR2 rs3087465 G>A, VEGF -2578C>A, -1498T>C, -634G>C and +936C>T polymorphisms may not play a role in the susceptibility of conotruncal heart defects.
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Affiliation(s)
- Enshi Wang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, China
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14
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Saxena R, Chawla YK, Verma I, Kaur J. Effect of IL-12B, IL-2, TGF-β1, and IL-4 polymorphism and expression on hepatitis B progression. J Interferon Cytokine Res 2014; 34:117-128. [PMID: 24161121 DOI: 10.1089/jir.2013.0043] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The hepatitis B virus (HBV) infection-induced chronic inflammation is considered to be the major etiological factor for HBV-related disease chronicity. Cytokines act as the key coordinators of the inflammatory responses involved in HBV disease pathogenesis. The present study assessed association among IL-12B(+1188), IL-2(-330), TGF-β1(-509), and IL-4(-590) genotypes; mRNA; and protein levels with HBV-hepatocellular carcinoma (HCC) risk in India. For this, 403 subjects (153 controls, 67 inactive HBV-carriers, 62 chronic-active HBV patients, 62 HBV-cirrhotics, and 59 HBV-HCC ssubjects) were enrolled in the study. The genotyping was carried by polymerase chain reaction (PCR)-restriction fragment length polymorphism (IL-12+1188A/C, IL-2-330T/G, and TGF-β1-509C/T), and allele specific (AS)-polymerase chain reaction (IL-4-590C/T). Enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction methods were used for assessing protein and the mRNA expression, respectively, of the mentioned cytokines. The study revealed that the IL-12B(+1188) CC genotype shared a significant positive association with hepatitis, among controls. While, in the case of IL-2(-330), both the TG and GG genotypes were not significantly associated with HCC risk. The TGF-β1(-509) TT genotype acted as a potential protective factor for cirrhosis and the HCC risk, among carriers. On the contrary, the IL-4(-590) CT genotype was found to be a vital protective factor for the development of hepatitis, among carriers. Besides, IL-12B, TGF-β1, and IL-2 seem to be majorly involved in the development of HCC, while, IL-4 might be responsible for the progression of the HBV disease till cirrhosis development. These initial findings are indicative of the vital role of genotypes and/or levels of IL-12B, IL-2, IL-4, and TGF-β1 in HBV disease chronicity in Indian population.
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Affiliation(s)
- Roli Saxena
- 1 Department of Biochemistry, Postgraduate Institute of Medical Education and Research , Chandigarh, India
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15
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Karimi-Googheri M, Daneshvar H, Nosratabadi R, Zare-Bidaki M, Hassanshahi G, Ebrahim M, Arababadi MK, Kennedy D. Important roles played by TGF-β in hepatitis B infection. J Med Virol 2013; 86:102-8. [PMID: 24009084 DOI: 10.1002/jmv.23727] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2013] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) which includes, fulminant, acute, chronic, asymptomatic, and occult HBV infection is the most prevalent virus that leads to human liver diseases. Chronic, asymptomatic, and occult infection can induce further sever diseases such as hepatocellular carcinoma (HCC) and cirrhosis of the liver. The underlying mechanisms that allow progression of the prolonged forms of the infection and subsequent HCC or cirrhosis of the liver are yet to be clarified. However, many researchers have suggested that immunological and genetic parameters may play important roles in the etiology of hepatitis B. Transforming growth factor beta (TGF-β) is an important cytokine with dual regulatory functions in the immune system and in the responses against viral infections. However, the pathways and mechanisms controlling these are not fully understood. The crucial roles of TGF-β in the development of Th17 and T regulatory lymphocytes, the main cell types involved in autoimmunity and destructive immune related diseases, have been documented and this provides insights into TGF-β function during hepatitis infection and subsequent HCC and cirrhosis of the liver. Recent findings also confirm that TGF-β directly alters hepatocyte function during hepatitis B, hence, the aim of this review is to address the current data regarding the association and status of TGF-β with hepatitis B infection and its related disorders including HCC and cirrhosis of the liver.
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16
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Wang Y, Chu X, Meng X, Zou F. Association of TGF-β1 -509C/T polymorphisms with breast cancer risk: evidence from an updated meta-analysis. Tumour Biol 2013; 35:935-42. [PMID: 23982878 DOI: 10.1007/s13277-013-1122-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Accepted: 08/14/2013] [Indexed: 01/18/2023] Open
Abstract
Epidemiological studies have evaluated the association between transforming growth factor-β1 (TGF-β1) -509C/T polymorphisms and breast cancer risk. However, the results remain conflicting rather than conclusive. The aim of this study was to comprehensively clarify the association between TGF-β1 -509C/T polymorphisms and breast cancer risk. All relevant studies were searched in the electronic databases. The potential sources of heterogeneity were detected with the chi-square-based Q test. The strength of associations between TGF-β1 -509C/T polymorphisms and breast cancer risk was measured by odds ratio (OR) and 95 % confidence intervals (CI). Publication bias was tested by Begg's test and Egger's test. A total of 10 studies including 10,913 cases and 14,187 controls were included in the meta-analysis. Overall, there was no evidence of significant association of TGF-β1 -509C/T polymorphisms with breast cancer risk (TT vs. CC [OR = 0.97, 95 % CI = 0.83-1.14]; CT vs. CC [OR = 1.05, 95 % CI = 0.90-1.22]; TT + CT vs. CC [OR = 0.99, 95 % CI = 0.91-1.08]; T allele vs. C allele [OR = 0.99, 95 % CI = 0.93-1.06]). Similar results were also found in the subgroup analyses by ethnicity and source of control. When stratified by estrogen receptor (ER) status, TT genotype and T allele were associated with a decreased ER-positive breast cancer risk (OR = 0.66, 95 % CI = 0.49-0.90 and OR = 0.85, 95 % CI = 0.75-0.96, respectively). The present meta-analysis results suggest that TGF-β1 -509C/T variants may not contribute to the risk of breast cancer overall. However, T allele may be a potential protective factor for developing ER-positive breast cancer. Well-designed studies with larger sample size were required to verify our findings further.
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Affiliation(s)
- Yadong Wang
- Henan Center for Disease Control and Prevention, Zhengzhou, 450016, People's Republic of China
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Li W, Wu H, Song C. TGF-β1 -509C/T (or +869T/C) polymorphism might be not associated with hepatocellular carcinoma risk. Tumour Biol 2013; 34:2675-81. [PMID: 23653379 DOI: 10.1007/s13277-013-0818-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 04/19/2013] [Indexed: 12/14/2022] Open
Abstract
Many studies have reported the role of transforming growth factor-β1 (TGF-β1) -509C/T or +869T/C polymorphism with hepatocellular carcinoma (HCC) risk. However, these studies have yielded conflicting results. Hence, we performed this meta-analysis to investigate the association between TGF-β1 -509C/T or +869T/C polymorphism and HCC. A total of 11 studies including 2,577 HCC cases and 4,107 controls were included in the meta-analysis. Overall, TGF-β1 -509C/T (or +869T/C) polymorphism was not associated with HCC risk (homogeneous co-dominant model: OR = 1.29, 95 % CI = 0.88-1.89; heterogeneous co-dominant model: OR = 1.15, 95 % CI = 0.91-1.45; dominant model: OR = 1.14, 95 % CI = 0.87-1.48; recessive model: OR = 1.15, 95 % CI = 0.89-1.49). In the subgroup analysis, TGF-β1 -509C/T (or +869T/C) polymorphism was significantly associated with HCC risk in Caucasians under the recessive model (OR = 1.65, 95 % CI = 1.07-2.55) but not in other genetic models. In addition, we did not observe significant association in Asians under all genetic models. In conclusion, our meta-analysis indicates that TGF-β1 -509C/T (or +869T/C) polymorphism was not associated with risk of HCC, although a marginal association was found for Caucasians. However, a study with the larger sample size is needed to further evaluate gene-environment interaction on the association.
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Affiliation(s)
- Weixing Li
- Laboratory Medicine, Zhejiang Provincial People's Hospital, Zhejiang, China,
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18
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Lee DH, Cho Y, Seo JY, Kwon JH, Cho EJ, Jang ES, Kwak MS, Cheong JY, Cho SW, Lee JH, Yu SJ, Yoon JH, Lee HS, Kim CY, Shin HD, Kim YJ. Polymorphisms near interleukin 28B gene are not associated with hepatitis B virus clearance, hepatitis B e antigen clearance and hepatocellular carcinoma occurrence. Intervirology 2013; 56:84-90. [PMID: 23343781 DOI: 10.1159/000342526] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Accepted: 08/10/2012] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Polymorphisms near the IL28B gene have been proposed to be strongly associated with treatment response and the rate of spontaneous clearance of hepatitis C virus infection, and treatment response of hepatitis B virus (HBV) infection. In this study, we aimed to determine whether these polymorphisms could affect natural courses of HBV infection. METHODS Genetic variations were identified through direct DNA sequencing using TaqMan assay in 1,439 patients with past or present HBV infection. Subjects included 404 spontaneously recovered patients, 313 chronic hepatitis B (CHB) patients, 305 liver cirrhosis (LC) patients and 417 hepatocellular carcinoma (HCC) patients. Three polymorphisms near the IL28B gene, rs8099917T>G, rs12979860C>T and rs12980275A>G, were identified. Associations between these polymorphisms and HBV clearance, hepatitis B e antigen (HBeAg) clearance as well as HCC occurrence among patients were analyzed using logistic regression analyses adjusted for age and gender. RESULTS There were no significant associations between these polymorphisms and the HBV clearance both in CHB and LC groups. Similarly, these polymorphisms showed no significant associations with HBeAg clearance and the occurrence of HCC either. DISCUSSION No significant association was identified between polymorphisms near the IL28B gene and the natural courses of chronic HBV infection, including the HBV clearance and HCC occurrence.
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Affiliation(s)
- Dong Hyeon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
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19
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Li GC, Ye QH, Dong QZ, Ren N, Jia HL, Qin LX. TGF beta1 and related-Smads contribute to pulmonary metastasis of hepatocellular carcinoma in mice model. J Exp Clin Cancer Res 2012; 31:93. [PMID: 23151305 PMCID: PMC3503772 DOI: 10.1186/1756-9966-31-93] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Accepted: 10/28/2012] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Recent studies indicate that Transforming Growth Factor beta (TGF β) correlated with pulmonary metastasis of cancers. However, the correlation between TGF β and pulmonary metastasis of hepatocellular carcinoma (HCC) is till unknown. METHODS We detected the in vitro and in vivo expression levels of TGF β1/Smads by Real-time PCR and Western blot in MHCC97-H and MHCC97-L cell lines, which are HCC cell lines and have higher and lower pulmonary metastatic potential respectively. RESULTS TGF β1 mRNA level in MHCC97-L tumors were higher than that in MHCC97-H tumors, (2.81±1.61 vs. 1.24±0.96, P=0.002), TGF β1 protein level in MHCC97-L tumors were also higher than that in MHCC97-H tumors (1.37±0.95 vs. 0.32±0.22, P<0.001). In addition, the TGF β1 mRNA level positively correlated with pulmonary metastasis, and the relations between TGF β1 and Smads were also found (R2=0.12 and 0.40, respectively). CONCLUSIONS Our results suggest that TGF β/ Smads promote pulmonary metastasis of HCC.
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Affiliation(s)
- Guo-Cai Li
- Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China
- GaoXin Hospital, Xi’an JiaoTong University, Xi’an, Shanxi Province, China
| | - Qing-Hai Ye
- Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Qiong-Zhu Dong
- Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Ning Ren
- Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Hu-Liang Jia
- Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Lun-Xiu Qin
- Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China
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20
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Qiu B, Wang X, Zhang P, Shi C, Zhang J, Qiu W, Wang W, Li D. Association of TNF-α promoter polymorphisms with the outcome of persistent HBV infection in a northeast Chinese Han population. Acta Biochim Biophys Sin (Shanghai) 2012; 44:712-8. [PMID: 22695741 DOI: 10.1093/abbs/gms046] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Tumor necrosis factor-α (TNF-α) plays an important role in the pathogenesis and clinical outcome of chronic hepatitis B virus (HBV) infection. The objective of this study was to evaluate the relationship between functional polymorphisms of TNF-α and different outcomes of persistent HBV infection in a northeast Chinese Han population. Here 189 HBV spontaneously recovered subjects (SR), 571 HBV-infected patients including 180 chronic hepatitis B (CHB), 196 liver cirrhosis (LC), and 195 hepatocellular carcinoma (HCC) individuals were enrolled in this study. All the samples were genotyped for TNF-α -857C/T and -863C/A using the polymerase chain reaction-restriction fragment length polymorphism method. The frequency of -857CC genotype was significantly higher in CHB and LC individuals compared with that of SR subjects (P= 0.03, OR = 1.57, 95% CI 1.04-2.39 and P= 0.03, OR = 1.57, 95% CI 1.04-2.35, respectively). A significant difference in the distribution of the allele -857C was observed for both CHB vs. SR (P= 0.01, OR = 1.52, 95% CI 1.08-2.13) and LC vs. SR (P= 0.02, OR = 1.47, 95% CI 1.06-2.04) cohorts. In addition, the frequency of -863AA genotype was significantly higher in CHB and LC patients than that of SR subjects (P= 0.01, OR = 3.90, 95% CI 1.35-11.23 and P= 0.01, OR = 3.83, 95% CI 1.34-10.96, respectively), and allele -863A frequency was significantly more common in CHB, LC, and HCC cohorts than that of SR controls (P= 0.004, OR = 1.72, 95% CI 1.19-2.50; P= 0.001, OR = 1.81, 95% CI 1.26-2.61 and P= 0.001, OR = 1.90, 95% CI 1.33-2.73, respectively). Our data also revealed that haplotype CA was strongly associated with persistent HBV infection. These results suggest an association between the TNF-α promoter variants and different outcomes of persistent HBV infection in the studied population.
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Affiliation(s)
- Bing Qiu
- Department of Gastroenterology, Heilongjiang Province Hospital, Harbin 150036, China.
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21
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Zhang CF, Wang ZW, Hou MX, Li K, Zhou X, Xia YH. Transforming Growth Factor β1-509C/T and +869T/C Polymorphisms on the Risk of Upper Digestive Tract Cancer: A Meta-Analysis Based on 10,917 Participants. Ann Hum Genet 2012; 76:363-76. [DOI: 10.1111/j.1469-1809.2012.00717.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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22
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Xiang TX, Cheng N, Li XN, Wu XP. Association between transforming growth factor-β1 polymorphisms and hepatocellular cancer risk: A meta-analysis. Hepatol Res 2012; 42:583-90. [PMID: 22257092 DOI: 10.1111/j.1872-034x.2011.00958.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM The association between transforming growth factor-β1 (TGF-β1) gene polymorphisms and hepatocellular cancer (HCC) risk has been widely reported, but results were somewhat controversial. To derive a more precise estimation of the relationship between TGF-β1 polymorphisms and HCC risk, we conducted a meta-analysis of all available studies relating the C-509T and/or T869C polymorphisms of the TGF-β1 gene to the risk of developing HCC. METHODS Two investigators independently searched the MEDLINE, PubMed, Web of Science, Embase, CNKI (China National Knowledge Infrastructure) and CBM (Chinese Biomedical Literature database) for the period up to August 2011. RESULT A total of nine case-control articles were identified. Five studies with 1825 cases and 2869 controls for C-509T polymorphism, and six studies with 536 cases and 1496 controls for T869C polymorphism were included. In the overall analysis, no significant association between the polymorphisms and risk of HCC was observed. Stratified analysis showed that significant association between C-509T polymorphism and HCC was present only in controls with liver disease (T vs. C: odds ratio [OR] = 0.769, 95% confidence interval [CI] = 0.661-0.895; TT vs. CC: OR = 0.570, 95% CI = 0.412-0.788; TT/TC vs. CC: OR = 0.668, 95% CI = 0.523-0.854; TT vs. TC/CC OR = 0.717, 95% CI = 0.550-0.934), but not in healthy controls. With respect to T869C polymorphism, only a decreased risk was found in recessive models in controls with liver disease. CONCLUSIONS This meta-analysis supports that the TGF-β1 C-509T polymorphism may act in a protecting role in HCC susceptibility in populations with related liver disease.
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Affiliation(s)
- Tian-Xin Xiang
- Department of Infectious Diseases, the First Hospital Affiliated of Nanchang University, Nanchang, China
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23
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Tomoda T, Nouso K, Sakai A, Ouchida M, Kobayashi S, Miyahara K, Onishi H, Nakamura S, Yamamoto K, Shimizu K. Genetic risk of hepatocellular carcinoma in patients with hepatitis C virus: a case control study. J Gastroenterol Hepatol 2012; 27:797-804. [PMID: 22004425 DOI: 10.1111/j.1440-1746.2011.06948.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM Chronic hepatitis C virus (HCV) infection is a well known risk factor for hepatocellular carcinoma (HCC). The aim of this study is to elucidate the genetic risk of development and recurrence of HCC in patients with HCV. METHODS A total of 468 patients with HCV, including 265 with HCC were enrolled. We genotyped 88 single nucleotide polymorphisms (SNPs) in 81 genes expected to influence hepatocarcinogenesis using the iPLEX assay. Risk of HCC was clarified by stratifying patients into risk groups based on the multiplied odds ratio (MOR) for SNPs associated with HCC, and the cumulative effects on the development and recurrence of HCC were analyzed. RESULTS Six SNPs associated with risk of HCC were identified (OR range: 0.29-1.76). These included novel SNPs for hepatocarcinogenesis with HCV CCND2 rs1049606, RAD23B rs1805329, CEP164 rs573455, and GRP78rs430397 in addition to the known SNPs MDM2 rs2279744 and ALDH2 rs671. MOR analysis revealed that the highest risk group exerted about a 19-fold higher relative OR compared with the lowest risk group (P = 1.08 × 10(-5)). Predicted 10-year HCC risk ranged from 1.7% to 96% depending on the risk group and the extent of fibrosis. Recurrence-free survival of radiofrequency ablation-treated HCC in the high risk group (n = 53) was lower than that of low risk group (n = 58, P = 0.038). CONCLUSION Single nucleotide polymorphisms of CCND2, RAD23B, GRP78, CEP164, MDM2, and ALDH2 genes were significantly associated with development and recurrence of HCC in Japanese patients with HCV.
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Affiliation(s)
- Takeshi Tomoda
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama city, Japan.
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YANG YAN, QIU XIAOQIANG, YU HONGPING, ZENG XIAOYUN, BEI CHUNHUA. TNF-α -863 polymorphisms and the risk of hepatocellular carcinoma. Exp Ther Med 2012; 3:513-518. [PMID: 22969921 PMCID: PMC3438725 DOI: 10.3892/etm.2011.418] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Accepted: 12/12/2011] [Indexed: 12/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common type of highly malignant tumor. Guangxi is an area of China characterized by a high incidence of HCC. Previous epidemiological studies have found that chronic infection with hepatitis B virus (HBV) is one of the major etiological risk factors for HCC in China. With the increased understanding of the host immune response against HBV and the pathogenesis of the virus, at present, greater attention is being given to the immune response of cytokine genes, as polymorphisms may have a major impact on the course and outcome of HBV infection. In the present study, we genotyped tumor necrosis factor-α (TNF-α) rs1800629 (-308G/A), rs1800630 (-863C/A); interleukin-1B rs1143627 (-31T/C); and transforming growth factor β1 (TGF-β1) rs1800469 (-509C/T) in a hospital-based study of 772 HCC cases and 852 cancer-free controls. The distribution of the frequency of TNF-α rs1800630 sites of CC, CA, AA were 65.67, 27.46 and 6.87% in the case group, respectively, as compared with 67.02, 29.58 and 3.40% in the controls, all with a statistical significance (P<0.05). The logistic regression analysis revealed that the variant rs1800630 AA genotypes were associated with a significantly increasing risk of HCC (OR=2.058, 95% CI 1.289-3.287), compared with the wild-type rs1800630 CC. Further stratified analyses showed that after stratification for history of alcohol drinking, in a subgroup of individuals without a history of drinking, the HCC risk in the group with the TNF-α rs1800630 A allele was 1.839 times higher than that in the group with TNF-α rs1800630 C (P<0.010). These findings suggest that TNF-α rs1800630 may contribute to the risk of HCC, however, these data require further validation.
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Affiliation(s)
- YAN YANG
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning
| | - XIAO-QIANG QIU
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning
- School of Public Health, Guilin Medical University, Guilin, Guangxi, P.R. China
| | - HONG-PING YU
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning
| | - XIAO-YUN ZENG
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning
| | - CHUN-HUA BEI
- School of Public Health, Guilin Medical University, Guilin, Guangxi, P.R. China
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Xin Z, Zhang W, Xu A, Zhang L, Yan T, Li Z, Wu X, Zhu X, Ma J, Li K, Li H, Liu Y. Polymorphisms in the potential functional regions of the TGF-β 1 and TGF-β receptor genes and disease susceptibility in HBV-related hepatocellular carcinoma patients. Mol Carcinog 2012; 51 Suppl 1:E123-31. [PMID: 22290546 DOI: 10.1002/mc.21876] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2011] [Revised: 09/30/2011] [Accepted: 12/27/2011] [Indexed: 12/21/2022]
Abstract
Hepatocellular carcinoma (HCC) is a disease of multiple etiologies caused by the accumulation of genetic and epigenetic defects. Current evidence indicates that the transforming growth factor beta (TGF-β) signaling pathway has a significant impact on different cellular process. Members of the TGF-β superfamily (TGF-β1, the type I TGF-β receptor [TβRI], type II TGF-β receptor [TβRII], and type III TGF-β receptor]) play an important role in tumorigenesis. Numerous studies show that genetic polymorphisms in TGF-β superfamily genes are associated with HCC in East Asian populations. We studied 16 single nucleotide polymorphisms (SNPs) in four genes (TGF-β1, TβRI, TβRII, and TβRIII) to examine their associations with hepatocarcinogenesis. A total of 1228 Chinese Han participants were enrolled in the study (881 control participants who were negative for all hepatitis B virus [HBV] serum markers and 347 case participants with HBV-related HCC). Genotyping was conducted using the TaqMan method. The results showed that the frequency of the rs1805110 T allele was significantly higher in the case group than in the control group (P = 0.034). After stratification, the results for rs1805110 remained significant in male participants (P = 0.005), but there was no statistical difference in females. In males, the frequency of the C-C-G-C-A haplotype resulting from SNPs rs1805110, rs2810904, rs1805112, rs284878, and rs1804506 in TβRIII was significantly lower in the case group than in the control group (P = 0.001), whereas the reverse was true for the T-C-G-C-A haplotype (P = 0.036). We conclude that the rs1805110T allele is associated with susceptibility to HBV-related HCC in males.
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Affiliation(s)
- Zhenhui Xin
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, PR China
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Lee JJ, Park SK, Kwon OS, Won IS, Kim DK, Jung YK, Ku YS, Kim YS, Choi DJ, Kim JH. Genetic polymorphism at codon 10 of the transforming growth factor-β1 gene in patients with alcoholic liver cirrhosis. THE KOREAN JOURNAL OF HEPATOLOGY 2011; 17:37-43. [PMID: 21494076 PMCID: PMC3304620 DOI: 10.3350/kjhep.2011.17.1.37] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Background/Aims Transforming growth factor beta1 (TGF-β1) is a key cytokine in the production of extracellular matrix. A genetic polymorphism at codon 10 of the TGF-β1 gene is associated with liver fibrosis. We investigated the effect of genetic polymorphisms at codon 10 on the development of alcoholic liver cirrhosis (ALC). Methods In total, 119 controls and 182 patients with ALC, were enrolled in the study. Clinical and laboratory data including total lifetime alcohol intake were collected at enrollment. The genotype at codon 10 was determined for each patient by single-strand conformation polymorphism. Results There were three types of genetic polymorphism at codon 10: homozygous proline (P/P), heterozygous proline/leucine (P/L), and homozygous leucine (L/L). Among the controls, the proportions of P/P, P/L, and L/L were 26.1%, 44.5%, and 29.4%, respectively in the ALC group, these proportions were 23.1%, 43.4%, and 33.5%, respectively. The genotype distribution did not differ between the controls and the ALC group. In the ALC group, age, total lifetime alcohol intake, and distribution of Child-Pugh class did not differ with the genotype. Of the male patients with ALC (n=164), the proportions of P/P, P/L, and L/L were 20.1%, 44.5%, and 35.4%, respectively the genotype distribution did not differ between the male controls and the male ALC patients. Conclusions The genotype at codon 10 in TGF-β1 does not appear to influence the development of ALC. Further study is needed to investigate other genetic factors that influence the development of ALC in patients with chronic alcohol intake.
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Affiliation(s)
- Jong Joon Lee
- Department of Internal Medicine, Gachon University of Medicine and Science, Incheon, Korea
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Daraei A, Salehi R, Salehi M, Emami MH, Janghorbani M, Jonghorbani M, Mohamadhashem F, Tavakoli H. Effect of rs6983267 polymorphism in the 8q24 region and rs4444903 polymorphism in EGF gene on the risk of sporadic colorectal cancer in Iranian population. Med Oncol 2011; 29:1044-9. [PMID: 21567271 DOI: 10.1007/s12032-011-9980-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Accepted: 05/04/2011] [Indexed: 12/13/2022]
Abstract
Colorectal cancer (CRC) is among the major causes of cancer-related morbidity, mortality, and human health problem worldwide. Single-nucleotide polymorphisms (SNPs) in different genes are reported to be effective in increased risk of CRC in different ethnic population. We conducted a case-control study in patients diagnosed with sporadic colorectal cancer (n = 115) and healthy controls based on colonoscopy evidences (n = 120).In this replicative study, we aimed to investigate the association of two previously reported polymorphisms, rs6983267 and rs4444903, with sporadic colorectal cancer in a subset of Iranian patients. Genotyping was performed via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. A significant relation was found between rs6983267 variant in the 8q24 region and colorectal cancer. The distribution of G/G genotypes among sporadic CRC patients was more frequent than that in the control group (P value = 0.001). The frequency of the G allele in the colorectal cancer patient group was also higher than that in the control group (65% vs. 48%; P value = 0.001). Compared with GG genotype, individuals with G/T and T/T genotypes had lower risk to develop sporadic CRC (OR = 0.357, 95% CI = 0.201-0.635). For the rs4444903 SNP, no significant association (P value = 0.149) was found with colorectal cancer risk. In conclusion, our findings suggest that the 8q24 rs6983267 SNP may play a pivotal role in the development of sporadic CRC in Iranian population. Therefore, it may be included as a potential genetic susceptibility marker for sporadic CRC.
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Affiliation(s)
- A Daraei
- Department of Biomedical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Guo W, Dong Z, Guo Y, Chen Z, Yang Z, Kuang G, Shan B. Polymorphisms of transforming growth factor-β1 associated with increased risk of gastric cardia adenocarcinoma in north China. Int J Immunogenet 2011; 38:215-24. [DOI: 10.1111/j.1744-313x.2010.00991.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Kim YJ, Kim HY, Kim JS, Lee JH, Yoon JH, Kim CY, Park BL, Cheong HS, Bae JS, Kim S, Shin HD, Lee HS. Putative association of transforming growth factor-alpha polymorphisms with clearance of hepatitis B virus and occurrence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Viral Hepat 2010; 17:518-526. [PMID: 19780938 DOI: 10.1111/j.1365-2893.2009.01205.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Previous studies showed that several genetic polymorphisms might influence the clinical outcome of chronic hepatitis B virus (HBV) infection, including HBV clearance or development of hepatocellular carcinoma (HCC). The aim of this study was to determine whether polymorphisms of the transforming growth factor-alpha (TGF-alpha) gene are associated with clinical outcome of HBV infection. A total of 1096 Korean subjects having either present or past evidence of HBV infection were prospectively enrolled between January 2001 and August 2003. Among 16 genetic variants in TGFA gene, nine variants were genotyped using TaqMan assay and the genetic association with HBV clearance and HCC occurrence was analysed. Statistical analyses revealed that TGFA+103461T>C, TGFA+106151C>G and TGFA-ht2 were marginally associated with clearance of HBV infection. However, only TGFA-ht2 retained significance after multiple correction (OR = 0.39, P(corr) = 0.007 in recessive model). Although no variants were significant after multiple correction, TGFA+88344G>A and TGFA+103461T>C were weakly associated in recessive model in the analysis of HCC occurrence. In addition, Cox relative hazards model also revealed that TGFA+88344G>A was associated with onset age of HCC occurrence in subjects (RH = 1.46, P(corr) = 0.04). TGF-alpha polymorphisms might be an important factor in immunity, progression of inflammatory process and carcinogenesis, which explains the variable outcome of HBV infection at least in part. Further biological evidence is warranted in the future to support these suggestive associations.
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Affiliation(s)
- Y J Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Chongno Gu, Seoul, Korea
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An Overview of Biomarkers and Molecular Signatures in HCC. Cancers (Basel) 2010; 2:809-23. [PMID: 24281095 PMCID: PMC3835106 DOI: 10.3390/cancers2020809] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2010] [Revised: 04/30/2010] [Accepted: 05/07/2010] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. Although most HCCs seem to originate from the accumulation of genetic abnormalities induced by various risk factors, underlying mechanisms of hepatocarcinogenesis remain unclear. Long-term survival of HCC patients is also poor, partly due to HCC recurrence. Although serum alpha-fetoprotein (AFP) level is a useful marker for the detection and monitoring of HCC, AFP levels may remain normal in the patients even with advanced HCC. To identify useful biomarkers for HCC, many studies have been conducted on molecular events such as genetic and epigenetic alterations, and gene expression. This review summarizes recent studies of potential molecular markers for diagnosis and monitoring metastasis or recurrence of HCC.
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Yu SK, Kwon OS, Jung HS, Bae KS, Kwon KA, Kim YK, Kim YS, Kim JH. Influence of transforming growth factor-beta1 gene polymorphism at codon 10 on the development of cirrhosis in chronic hepatitis B virus carriers. J Korean Med Sci 2010; 25:564-9. [PMID: 20357999 PMCID: PMC2844609 DOI: 10.3346/jkms.2010.25.4.564] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2009] [Accepted: 07/01/2009] [Indexed: 12/22/2022] Open
Abstract
Transforming growth factor (TGF)-beta1 is a key cytokine producing extracellular matrix. We evaluated the effect of TGF-beta1 gene polymorphism at codon 10 on the development of cirrhosis in patients with chronic hepatitis B. One hundred seventy eight patients with chronic hepatitis (CH, n=57) or liver cirrhosis (LC, n=121), who had HBsAg and were over 50 yr old, were enrolled. The genotypes were determined by single strand conformation polymorphism. There were no significant differences in age and sex ratio between CH and LC groups. HBeAg positivity and detection rate of HBV DNA were higher in LC than in CH groups (P=0.055 and P=0.003, respectively). There were three types of TGF-beta1 gene polymorphism at codon 10: proline homozygous (P/P), proline/leucine heterozygous (P/L), and leucine homozygous (L/L) genotype. In CH group, the proportions of P/P, P/L, and L/L genotype were 32%, 51%, and 17%, respectively. In LC group, the proportions of those genotypes were 20%, 47%, and 33%, respectively. The L/L genotype was presented more frequently in LC than in CH groups (P=0.017). Multivariate logistic regression analysis confirms that detectable HBV DNA (odds ratio [OR]: 3.037, 95% confidence interval [CI]: 1.504-6.133, P=0.002) and L/L genotype (OR: 3.408, 95% CI: 1.279-9.085, P=0.014) are risk factors for cirrhosis.
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Affiliation(s)
- Sang Kyun Yu
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Oh Sang Kwon
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Hyuk Sang Jung
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Kyung Suk Bae
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Kwang An Kwon
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Yu Kyung Kim
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Yun Soo Kim
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Ju Hyun Kim
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
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Park TJ, Chun JY, Bae JS, Kim JSY, Lee JS, Pasaje CF, Park BL, Cheong HS, Lee HS, Kim YJ, Shin HD. Putative Association of ITGB1 Haplotype with the Clearance of HBV Infection. Genomics Inform 2010. [DOI: 10.5808/gi.2010.8.1.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
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Association of a variant in MIR 196A2 with susceptibility to hepatocellular carcinoma in male Chinese patients with chronic hepatitis B virus infection. Hum Immunol 2010; 71:621-6. [PMID: 20188135 DOI: 10.1016/j.humimm.2010.02.017] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2009] [Revised: 02/05/2010] [Accepted: 02/18/2010] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions as tumor suppressors and oncogenes. Recent studies have implicated that the rs11614913 SNP in MIR196A2 was associated with susceptibility of lung cancer, congenital heart disease, breast cancer and shortened survival time of nonsmall cell lung cancer. To assess whether this polymorphism is associated with susceptibility to and clinicopathologic characteristics of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), a total of 560 patients with chronic HBV infection and 391 healthy volunteers were enrolled, and MIR196A2 polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). In our study group, there was no significant association between MIR196A2 polymorphism and the risk of HBV-related HCC in all subjects, however, the risk of HCC was significantly higher with MIR196A2 rs11614913 CC genotype or C allele compared with those with the TT genotype or T allele in male patients. Furthermore, in a subsequent analysis of the association between this polymorphism and clinicopathologic characteristics, there was still no significant difference in both the distribution of genotype or allelic frequency. However, we observed that the T allele was significantly more frequent in male HCC patients with lymphatic metastasis. Our results suggested that MIR196A2 polymorphism was associated with susceptibility to HBV-related HCC in a male Chinese population.
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Qi P, Wang H, Chen YM, Sun XJ, Liu Y, Gao CF. No association of EGF 5'UTR variant A61G and hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. Pathology 2010; 41:555-60. [PMID: 19900104 DOI: 10.1080/00313020903071603] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVE Epidermal growth factor (EGF) has many biological functions, including mitogenesis, tumorigenesis, and proliferation of epidermal tissues. Previous studies have reported that the EGF +61 (A/G) single nucleotide polymorphism in the 5'-untranslated region of the EGF gene is functional, and is associated with development of hepatocellular carcinoma (HCC) in liver cirrhosis and various malignancy. Our aim was to investigate whether EGF gene A61G polymorphism could be implicated in susceptibility to and/or clinicopathological characteristics of HCC in Chinese patients with chronic hepatitis B virus (HBV) infection. METHODS This polymorphism was studied in 387 patients with chronic HBV infection and in 208 healthy volunteers using restriction fragment-length polymorphism. The patients were divided into two groups: those without (n = 172) and those with HCC (n = 215). These 215 HCC patients with chronic HBV infection were designated as cases, and the remaining 172 patients without HCC served as controls. RESULTS There were no significant differences in EGF genotype or allelic frequencies between cases and controls nor was EGF genotype or allelic frequencies associated with tumour number, size, growth phase, stage, and invasiveness. We also found ethnic heterogeneity in the functional EGF polymorphism. CONCLUSIONS The present results show that although EGF gene A61G polymorphism is associated with development of HCC in liver cirrhosis, it is not sufficient for HCC in Chinese patients with chronic HBV infection.
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Affiliation(s)
- Peng Qi
- Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai. PR China
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35
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Okamoto K, Ishida C, Ikebuchi Y, Mandai M, Mimura K, Murawaki Y, Yuasa I. The genotypes of IL-1 beta and MMP-3 are associated with the prognosis of HCV-related hepatocellular carcinoma. Intern Med 2010; 49:887-95. [PMID: 20467172 DOI: 10.2169/internalmedicine.49.3268] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND AND AIM Cytokines and matrix metalloproteinases (MMPs) are involved in tumor growth, invasion, and remote metastasis in various cancers. Recently, functional gene polymorphisms in these cytokines and MMPs have been found, and some reports have revealed an association between these polymorphisms and the prognosis of various cancers. In this study, we examined the relationship between the gene polymorphisms of interleukin 1 beta (IL-1b), IL-1 receptor antagonist (IL-1 RN), transforming growth factor beta 1 (TGF-b1), MMP-1, MMP-3, and MMP-9 and the prognosis of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODS We enrolled 92 HCV-related HCC patients in the study, and gene polymorphisms of IL-1b -31 C/T, IL-1 RN variable number of tandem repeats (VNTR), TGF-b1 +869 C/T, MMP-1 -1,607 1G/2G, MMP-3 -1,171 5A/6A, and MMP-9 -1,562 C/T were analyzed. RESULTS In HCC clinical features, TGF-b1 C carriers and MMP-3 5A carriers had significantly larger HCC diameters than TGF-b1 T and MMP-3 6A homozygotes. In HCC prognosis, IL-1b T homozygotes and MMP-3 5A carriers had a significantly poorer prognosis than IL-1b C carriers and MMP-3 6A homozygotes. Those with a combination of IL-1b T homozygosity and MMP-3 5A had synergistically poorer HCC prognosis. CONCLUSION The IL-1b -31 T allele and MMP-3 5A allele are cooperative risk factors for poor prognosis in HCC patients, suggesting that these gene polymorphisms might be potential markers for predicting the prognosis of HCC patients.
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Affiliation(s)
- Kinya Okamoto
- The Second Department of Internal Medicine, Tottori University School of Medicine, Yonago.
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36
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Wei BB, Xi B, Wang R, Bai JM, Chang JK, Zhang YY, Yoneda R, Su JT, Hua LX. TGFbeta1 T29C polymorphism and cancer risk: a meta-analysis based on 40 case-control studies. ACTA ACUST UNITED AC 2009; 196:68-75. [PMID: 19963138 DOI: 10.1016/j.cancergencyto.2009.09.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2009] [Revised: 08/15/2009] [Accepted: 09/20/2009] [Indexed: 01/27/2023]
Abstract
Transforming growth factor-beta1 (TGFbeta1) plays a significant role in regulating cellular proliferation and apoptosis. The TGFbeta1 T29C polymorphism reportedly affects cancer risk, but pertinent studies offer conflicting results. We therefore performed a meta-analysis based on 40 studies from 32 publications, assessing the strength of the association using odds ratios with 95% confidence intervals. Overall, no evidence has indicated that individuals carrying CC or CT genotypes had significantly increased cancer risks, compared with TT genotype carriers [CC vs. TT: odds ratio (OR)=1.10, 95% confidence interval (95% CI)=1.00-1.21, P=0.06; CT vs. TT: OR=1.07, 95% CI=0.99-1.16, P=0.09). However, stratified analysis by cancer type and ethnicity indicated a significantly increased risk of prostate cancer (CT vs. TT: OR=1.28, 95% CI=1.01-1.61, P=0.04) and cancer in those of Asian descent (CC vs. TT: OR=1.26, 95% CI=1.03-1.53, P=0.02; CT vs. TT: OR=1.20, 95% CI=1.01-1.43, P=0.04). This association was also observed in the dominant model for prostate cancer. Although not all bias could be eliminated, this meta-analysis suggested that TGFbeta1 29C was a low-penetrant risk factor for prostate cancer and cancer in Asians. A larger single study is still required to evaluate any association with other types of cancer or in other populations.
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Affiliation(s)
- Bing-Bing Wei
- Department of Urology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
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37
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Kim YS, Cheong JY, Cho SW, Lee KM, Hwang JC, Oh B, Kimm K, Lee JA, Park BL, Cheong HS, Shin HD, Kim JH. A functional SNP of the Interleukin-18 gene is associated with the presence of hepatocellular carcinoma in hepatitis B virus-infected patients. Dig Dis Sci 2009; 54:2722-8. [PMID: 19757044 DOI: 10.1007/s10620-009-0970-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2009] [Accepted: 08/24/2009] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIM The natural course of hepatitis B virus (HBV) infection is likely related to host immune factors. Interleukin-18 (IL-18) plays a significant role in immune defense. This study was undertaken to determine the association between the presence of hepatocellular carcinoma (HCC) and single-nucleotide polymorphisms (SNPs) in the IL-18 gene in HBV-infected patients. METHODS Between March 2002 and December 2004, 730 Korean subjects were enrolled in two different groups: (1) chronic carrier without HCC (n=637) and (2) HCC (n=93). We analyzed SNPs at four polymorphic sites in the IL-18 gene at positions -667G>T, -148G>C, +8925C>G, and +13925A>C in the study subjects. To evaluate the functional significance of SNPs in the IL-18 gene promoter region, we performed a reporter gene assay in HepG2 and Hep3B cells transfected with different alleles. RESULTS The IL-18 -148C allele, +8925G allele, +13925C allele, and haplotype 3 (TCGC) were associated with the presence of HCC in codominant and dominant models. Furthermore, functional analyses using the reporter gene assay revealed that the -148C allele conferred significantly lower promoter activity. CONCLUSIONS This study indicates that the -148C, +8925G, and +13925C alleles of the IL-18 gene are associated with the presence of HCC and the 148G>C SNP is functionally important in determining disease outcome.
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Affiliation(s)
- Yong Seok Kim
- Department of Biochemistry and Molecular Biology, Hanyang University College of Medicine, Seoul, South Korea
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Andreana L, Isgrò G, Pleguezuelo M, Germani G, Burroughs AK. Surveillance and diagnosis of hepatocellular carcinoma in patients with cirrhosis. World J Hepatol 2009; 1:48-61. [PMID: 21160965 PMCID: PMC2998953 DOI: 10.4254/wjh.v1.i1.48] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2009] [Revised: 09/11/2009] [Accepted: 09/18/2009] [Indexed: 02/06/2023] Open
Abstract
Early identification of hepatocellular carcinoma (HCC) is more frequent because of surveillance programs for HCC worldwide. The optimal strategy of surveillance in cirrhosis is a current topical issue. In terms of diagnosis, recent advances in non-invasive imaging technology, including various techniques of harmonic ultrasound, new ultrasound contrast agents, multi-slice helical computed tomography and rapid high quality magnetic resonance, have all improved the accuracy of diagnosis. Consequently the role of liver biopsy in diagnosis of HCC has declined. The imaging diagnosis relies on the hallmark of arterial hypervascularity with portal venous washout. However, with recent advances in genomics and proteomics a great number of potential serum and tissue markers have been identified and are being developed as new candidate markers for both diagnosis and prognosis of hepatocellular carcinoma, and may increase the need for liver biopsy.
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Affiliation(s)
- Lorenzo Andreana
- Lorenzo Andreana, Graziella Isgrò, Maria Pleguezuelo, Giacomo Germani, Andrew K Burroughs, The Royal Free Sheila Sherlock Liver Center, Departement of Surgery, Royal Free Hospital, London, NW3 2QG, United Kingdom
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Guan X, Zhao H, Niu J, Tang D, Ajani JA, Wei Q. The VEGF -634G>C promoter polymorphism is associated with risk of gastric cancer. BMC Gastroenterol 2009; 9:77. [PMID: 19835575 PMCID: PMC2771032 DOI: 10.1186/1471-230x-9-77] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2009] [Accepted: 10/16/2009] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Both TGF-beta1 and VEGF play a critic role in the multiple-step process of tumorgenesis of gastric cancer. Single nucleotide polymorphisms (SNPs) of the TGFB1 and VEGF genes have been associated with risk and progression of many cancers. In this study, we investigated the association between potentially functional SNPs of these two genes and risk of gastric cancer in a US population. METHODS The risk associated with genotypes and haplotypes of four TGFB1 SNPs and four VEGF SNPs were determined by multivariate logistic regression analysis in 171 patients with gastric cancer and 353 cancer-free controls frequency-matched by age, sex and ethnicity. RESULTS Compared with the VEGF-634GG genotype, the -634CG genotype and the combined -634CG+CC genotypes were associated with a significantly elevated risk of gastric cancer (adjusted OR = 1.88, 95% CI = 1.24-2.86 and adjusted OR = 1.56, 95% CI = 1.07-2.27, respectively). However, none of other TGFB1 and VEGF SNPs was associated with risk of gastric cancer. CONCLUSION Our data suggested that the VEGF-634G>C SNP may be a marker for susceptibility to gastric cancer, and this finding needs to be validated in larger studies.
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Affiliation(s)
- Xiaoxiang Guan
- Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
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Wu GY, Hasenberg T, Magdeburg R, Bönninghoff R, Sturm JW, Keese M. Association between EGF, TGF-beta1, VEGF gene polymorphism and colorectal cancer. World J Surg 2009; 33:124-9. [PMID: 19011936 DOI: 10.1007/s00268-008-9784-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Up to the present, EGF 61 A/G, TGF-beta1 -509 T/C, and VEGF 936 T/C gene polymorphisms have been analyzed in other cancer entities than colorectal cancer. We have now investigated the frequency of these gene polymorphisms among colorectal cancer patients. MATERIAL AND METHODS A total of 157 colorectal cancer patients and 117 cancer-free healthy people were recruited at the Surgical Department of the Universitätsklinikum Mannheim. All patients and healthy people are Caucasians. Genomic DNA was isolated from peripheral blood, and gene polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS The distribution of EGF 61 G/G homozygotes among colorectal cancer patients was more frequent than that in the control group (33.1% versus 11.1%; Odds Ratio [OR]=3.962; 95% Confidence Interval [CI]=2.036-7.708). The frequency of the "G" allele in the colorectal cancer patient group was also higher than that in the control group (51.3% versus 33.3%; OR=2.105; 95% CI=1.482-2.988). No difference could be found for the TGF-beta1 and VEGF genotypes among colorectal cancer patients and healthy controls. CONCLUSIONS The EGF 61 G/G genotype and the G allele are significantly related to colorectal cancer. The TGF-beta1 -509 T/C and VEGF 936 T/C gene polymorphisms are not related to colorectal cancer.
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Affiliation(s)
- Guo-yang Wu
- Department of General Surgery, Zhongshan Hospital, Xiamen University, Xiamen, People's Republic of China.
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Kim YJ, Lee HS. [Genetic epidemiological study on single nucleotide polymorphisms associated with hepatocellular carcinoma in patients with chronic HBV infection]. THE KOREAN JOURNAL OF HEPATOLOGY 2009; 15:7-14. [PMID: 19346781 DOI: 10.3350/kjhep.2009.15.1.7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Hepatocellular carcinoma (HCC) is associated with hepatitis B virus (HBV) as an etiologic agent in 80% of cases, and is the major cause of death among HBV carriers. Family history of HCC is a known risk factor for the development of HCC among chronically HBV infected patients; therefore, genetic factors are likely to modify the risk of HCC. However, the genetic factors that determine progression to HCC remain mostly to be recovered. It is estimated that there are millions of single nucleotide polymorphisms (SNPs) within human genome and they are likely to explain much of the genetic diversity of individuals. In this review, the natural history of HBV infection and host genetic factors related to HCC, study design and target gene selection for the detection of SNPs related to the occurrence of HCC were discussed. Also, several SNPs or haplotypes, which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection, were reviewed. Especially, recent studies in Korea, one of the HBV endemic areas, were discussed. Screening of these polymorphisms might be useful in clinical practice to stratify the lower or higher risk group for HCC and might modify the design of HCC surveillance programs in patients with chronic HBV infection, if further genetic susceptibilities are identified. The ongoing studies of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HCC, but may also provide a novel rationale for new methods of diagnosis and therapeutic strategies.
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Affiliation(s)
- Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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Gressner OA, Jafari S, Erkens M, Gao C, Stanzel S, Gressner AM. Evaluation of serum percent trisialotransferrin as potential predictive biomarker of hepatocellular dedifferentiation in chronic liver disease. Clin Chim Acta 2009; 403:188-93. [DOI: 10.1016/j.cca.2009.02.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2009] [Revised: 02/23/2009] [Accepted: 02/24/2009] [Indexed: 11/24/2022]
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Gressner OA, Gao C, Rehbein K, Lahme B, Siluschek M, Berg T, Müller T, Gressner AM. Elevated concentrations of 15-deoxy-Delta12,14-prostaglandin J2 in chronic liver disease propose therapeutic trials with peroxisome proliferator activated receptor gamma-inducing drugs. Liver Int 2009; 29:730-5. [PMID: 19018984 DOI: 10.1111/j.1478-3231.2008.01895.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND/AIMS Current knowledge confers a crucial role to connective tissue growth factor (CTGF/CCN2) in hepatic fibrogenesis. Hepatocytes are likely to be the major cellular source of CTGF in the liver in which CTGF is sensitively upregulated by TGF-beta. Recently, we demonstrated that the methylxanthine derivate caffeine leads to an upregulation of peroxisome proliferator activated receptor gamma (PPARgamma) expression in hepatocytes, thus sensitizing these cells to the well-known inhibitory effect of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15-d-PGJ(2)) on CTGF expression. However, upregulation of the receptor alone is not sufficient per se; its physiological ligand 15-d-PGJ(2) is required to exert an inhibitory effect on transforming growth factor-beta (TGF-beta) target genes such as CTGF. METHODS This study compared serum concentrations of 15-d-PGJ(2) in Caucasian patients with fibrotic liver diseases (n=289), Caucasian controls (n=136) and Caucasian non-liver disease (NLD) sick (n=307), as well as of Chinese patients with hepatocellular carcinoma (HCC) (n=43) and Chinese healthy controls (n=63) in order to characterize their suitability for therapeutic approaches with PPARgamma-inducing (i.e. CTGF inhibitory) drugs such as caffeine. RESULTS The presented data showed that Caucasian patients with ongoing hepatic fibrogenesis (mean 6.2+/-5.9 microg/L) displayed strikingly higher serum concentrations of 15-d-PGJ(2) than healthy probands (mean 2.3+/-1.0) and Caucasian patients with NLD (mean 2.7+/-1.4 microg/L). Similar results were found in Chinese patients with fully developed HCC (mean 1.3+/-0.7 microg/L) compared with Chinese healthy controls (mean 0.4+/-0.2 microg/L). CONCLUSIONS In conclusion, our data thus proposed an increased suitability of these patient groups for therapeutic approaches with drugs inducing PPARgamma expression, such as methylxanthine derivates.
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Affiliation(s)
- Olav A Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen, Germany.
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44
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Lee SK, Kim MH, Cheong JY, Cho SW, Yang SJ, Kwack K. Integrin alpha V polymorphisms and haplotypes in a Korean population are associated with susceptibility to chronic hepatitis and hepatocellular carcinoma. Liver Int 2009; 29:187-95. [PMID: 18694400 DOI: 10.1111/j.1478-3231.2008.01843.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND/AIMS Integrins are cell surface receptors for extracellular matrix (ECM) proteins that initiate signalling pathways that modulate proliferation, survival, invasion or metastasis. Consequently, integrins are potential targets for the treatment of cancer. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in integrin alpha(V) (ITGAV) in a Korean population were associated with chronic hepatitis B virus (HBV) infection and HBV-infected hepatocellular carcinoma (HCC). PATIENTS AND METHODS Thirteen ITGAV SNPs in 111 cases of chronic HBV infection, 86 cases of HBV-infected HCC and 107 cases of acute self-limited HBV infection were genotyped using Illumina's Sentrix array matrix (SAM) chip. RESULTS The ITGAV intron SNPs rs9333289 and rs11685758, the 3'-untranslated region SNP rs1839123 and haplotype 3 (T-T-A) were associated with enhanced susceptibility to HBV-infected HCC (OR=1.75-2.42; P=0.02-0.05), while the intron SNP rs2290083 was associated with both chronic infection and HBV-infected HCC (OR=1.73-2.01; P=0.01-0.04). In addition, both rs2290083 and ht1 (C-C-G) were associated with the age at which chronic infection occurred, as determined by Cox relative hazard analysis (RH=1.39-1.62, P=0.04-0.01) CONCLUSION ITGAV SNPs and haplotypes may be genetic factors that increase the susceptibility of Koreans to chronic HBV infection and HBV-infected HCC.
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Affiliation(s)
- Seung Ku Lee
- Medical Genomics Laboratory, Graduate School of Life Science and Biotechnology, Pochon CHA University, SeongNam, Korea
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Park HJ, Ye YM, Hur GY, Kim SH, Park HS. Association between a TGFβ1 promoter polymorphism and the phenotype of aspirin-intolerant chronic urticaria in a Korean population. J Clin Pharm Ther 2008; 33:691-7. [DOI: 10.1111/j.1365-2710.2008.00957.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Pleguezuelo M, Germani G, Marelli L, Xiruochakis E, Misseri M, Manousou P, Arvaniti V, Burroughs AK. Evidence-based diagnosis and locoregional therapy for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2008; 2:761-84. [PMID: 19090737 DOI: 10.1586/17474124.2.6.761] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Early identification of hepatocellular carcinoma (HCC) is crucial to improving the results of therapy and for patients to be eligible for liver transplantation. Recent advances in noninvasive imaging technology include various techniques of harmonic ultrasound, new ultrasound contrast agents, multislice helical computed tomography and rapid high-quality magnetic resonance. The imaging diagnosis relies on the hallmark of arterial hypervascularity with portal venous washout. Since the use of better radiological techniques has improved the accuracy of noninvasive diagnosis, the role of liver biopsy in the diagnosis of HCC has declined. With recent advances in genomics and proteomics, a great number of potential markers have been identified and developed as new candidate markers for HCC. Locoregional therapies currently constitute the best options for early nonsurgical treatment of HCC. Percutaneous ethanol injection shows similar results to resection surgery for single tumors less than 3 cm in diameter. Radiofrequency ablation is superior to percutaneous ethanol injection in terms of local recurrence. Transarterial chemoembolization is currently the most common approach for the management of HCC without curative options since it improves patient survival, but the optimal embolizing agent, length of interval between sessions and whether the chemotherapeutic agent has any effect have not yet been determined. Combining transarterial chemoembolization with antiangiogenic agents, as well as with other techniques, such as radiofrequency ablation, may improve the results. Injection of radioisotopes such as yttrium-90, via the hepatic artery, may be particularly useful in patients with portal vein thrombosis. Comparisons with other transarterial techniques are needed.
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Affiliation(s)
- Maria Pleguezuelo
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital, Pond Street, London, NW3 2QG, UK.
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Park NH, Chung YH. [Molecular mechanisms of hepatitis B virus-associated hepatocellular carcinoma]. THE KOREAN JOURNAL OF HEPATOLOGY 2008; 13:320-40. [PMID: 17898549 DOI: 10.3350/kjhep.2007.13.3.320] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant diseases in the world. The hepatitis B virus (HBV) replicates non-cytopathically in hepatocytes, and most of the liver injury associated with this infection reflects the immune response. Epidemiological studies have clearly demonstrated that a chronic HBV infection is a major etiological factor in the development of HCC. The pathogenesis of HBV-associated HCC has been studied extensively, and the molecular changes during the malignant transformation have been identified. The main carcinogenic mechanism of HBV-associated HCC is related to the long term-inflammatory changes caused by a chronic hepatitis B infection, which might involve the integration of the HBV. Integration of the HBV DNA into the host genome occurs at the early steps of clonal tumorous expansion. The hepatitis B x protein (HBx) is a multifunctional regulatory protein that communicates directly or indirectly with a variety of host targets, and mediates many opposing cellular functions, including its function in cell cycle regulation, transcriptional regulation, signaling, encoding of the cytoskeleton and cell adhesion molecules, as well as oncogenes and tumor suppressor genes. Continued study of the mechanisms of hepatocarcinogenesis will refine our current understanding of the molecular and cellular basis for neoplastic transformations in the liver. This review summarizes the current knowledge of the mechanisms involved in HBV-associated hepatocarcinogenesis.
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Affiliation(s)
- Neung Hwa Park
- Department of Internal Medicine, University of Ulsan College of Medicine, Biomedical Research Center, Ulsan University Hospital, Ulsan, Korea
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Jiang ZL. Advances in research on genetic predisposition to liver cirrhosis after hepatitis B virus infection. ACTA ACUST UNITED AC 2008; 6:1074-9. [DOI: 10.3736/jcim20081019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Falleti E, Fabris C, Toniutto P, Fontanini E, Cussigh A, Bitetto D, Fornasiere E, Avellini C, Minisini R, Pirisi M. TGF-beta1 genotypes in cirrhosis: relationship with the occurrence of liver cancer. Cytokine 2008; 44:256-61. [PMID: 18809335 DOI: 10.1016/j.cyto.2008.08.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2008] [Revised: 07/22/2008] [Accepted: 08/08/2008] [Indexed: 02/09/2023]
Abstract
This study aimed to verify whether specific single nucleotide polymorphisms (SNPs) of the transforming growth factor-beta1 (TGF-beta1) may predispose to end-stage liver disease and/or hepatocellular carcinoma (HCC). One hundred eighty-eight consecutive patients transplanted for liver cirrhosis (HBV N=21, HCV N=68, alcoholic N=55 and others N=23) and a control group of 140 healthy blood donors were investigated. Four SNPs were studied by restriction fragment length assays: -800G>A, -509C>T, Leu10Pro and Arg25Pro. Patients were found to possess the -509T/ * (TT 53/188, CT 85/188, CC 50/188 vs TT 22/140, CT 61/140, CC 57/140; p<0.002) and Arg25Pro C/ * genotypes (CC 1/188, CG 31/188, GG 156/188 vs CC 0/140, CG 13/140, GG 127/140; p<0.05) more frequently than controls. Patients with cirrhosis complicated by HCC possessed more frequently the Leu10Pro T/ * genotype than patients without HCC (TT 20/54, CT 26/54, CC 8/54 vs TT 31/134, CT 69/134, CC 34/134; p<0.05). The analysis of molecular variance detected significant genotypic differentiations between controls and cirrhotics but not between cirrhotics with or without HCC. In conclusion, TGF-beta1 SNPs probably facilitate the development of liver cirrhosis, while they seem to have a limited role in predicting the occurrence of HCC.
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Wei YS, Xu QQ, Wang CF, Pan Y, Liang F, Long XK. Genetic variation in transforming growth factor-beta1 gene associated with increased risk of esophageal squamous cell carcinoma. ACTA ACUST UNITED AC 2008; 70:464-9. [PMID: 17990985 DOI: 10.1111/j.1399-0039.2007.00935.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The genetic alterations leading to esophageal squamous cell carcinoma (ESCC) are gradually being discovered. A wide variety of genes have been associated with ESCC development as well as tumor progression. Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine; it promotes tumor growth and metastasis in later stages of of cancer development. Variations in the DNA sequence in the TGF-beta1 gene may lead to altered TGF-beta1 production and/or activity, and so this can modulate an individual's susceptibility to ESCC. To test this hypothesis, we investigated the association of the TGF-beta1 gene -509 C/T and 869 T/C (Leu10Pro) polymorphisms and their haplotypes with the risk of ESCC. 247 patients with ESCC and 260 age- and sex-matched controls were studied using a polymerase chain reaction-restriction fragment length polymorphism. There were significant differences in the genotype and allele distribution of 869 T/C polymorphism of the TGF-beta1 gene among cases and controls. The 869 TC and CC genotypes were associated with a significantly increased risk of ESCC as compared with the 869 TT genotypes [odds ratio (OR) = 1.882, 95% confidence interval (CI) 1.212-2.923, P = 0.005 and OR = 2.099, 95% CI 1.288-3.421, P = 0.003, respectively]. Consistent with the results of the genotyping analyses, the -509 T/869 C haplotype was associated with a significantly increased risk of ESCC as compared with the -509 C/869 T haplotype (OR = 1.463; 95% CI 1.120-1.912; P = 0.005). This study shows for the first time that TGF-beta1 gene 869 T/C polymorphism may contribute to a genetic risk factor for ESCC in a Chinese population.
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Affiliation(s)
- Y-S Wei
- Center of Clinical Laboratory, Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi, China.
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