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Kar S, Verma D, Mehrotra S, Prajapati VK. Reconfiguring the immune system to target cancer: Therapies based on T cells, cytokines, and vaccines. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2025; 144:77-150. [PMID: 39978976 DOI: 10.1016/bs.apcsb.2024.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Over the years, extensive research has been dedicated to performing in-depth analysis of cancer to uncover the intricate details of its nature - including the types of cancer, causative agents, stimulators of disease progression, factors contributing to poor prognosis, and efficient therapies to restrict the metastatic aggressiveness. This chapter highlights the mechanisms through which different arms of the host immune system - namely cytokines, lymphocytes, antigen-presenting cells (APCs) -can be mobilized to eradicate cancer. Most malignant tumors are either poorly immunogenic, or are harbored in a highly immuno-suppressive microenvironment. This is why reinforcing the host's anti-tumor defenses, through infusion of pro-inflammatory cytokines, tumor antigen-loaded APCs, and anti-tumor cytotoxic cells has emerged as a viable treatment option against cancer. The chapter also highlights the ongoing preclinical and clinical studies in different malignancies and the outcome of various therapies. Although these methods are not foolproof, and antigen escape variants can still evade or develop resistance to customized therapies, they achieve disease stabilization in several cases when conventional treatments fail. In many instances, combination therapies involving cytokines, T cells, and vaccinations prove more effective than monotherapies. The limitations of the current therapies are also discussed, along with ongoing modifications aimed at improving efficacy.
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Affiliation(s)
- Sramona Kar
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Divya Verma
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
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Prommee N, Itharat A, Thongdeeying P, Makchuchit S, Pipatrattanaseree W, Tasanarong A, Ooraikul B, Davies NM. Exploring in vitro anti-proliferative and anti-inflammatory activities of Prasachandaeng remedy, and its bioactive compounds. BMC Complement Med Ther 2022; 22:217. [PMID: 35953870 PMCID: PMC9373486 DOI: 10.1186/s12906-022-03678-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 07/13/2022] [Indexed: 11/20/2022] Open
Abstract
Background Prasachandaeng (PSD) remedy has been empirically used in Thai traditional medicine to treat fever in bile duct and liver and cancer patients through Thai folk doctors. However, there have been no scientific reports on the bioactive compounds and bioactivities related to inflammation-associated carcinogenesis or cytotoxicity against cancer cell lines. In this study, we investigated the chemical content of the remedy, and evaluated its cytotoxic activity against two cancer cell lines in comparison with a non-cancerous cell line and determined tumor necrosis factor-alpha (TNF-α) production in a murine macrophage cell line (RAW 264.7) to evaluate anti-inflammatory activity. A novel HPLC method was used for quality control of its chemical content. Methods Pure compounds from the EtOH extract of D. cochinchinensis were isolated using bioassay-guided fractionation and chemical content of the PSD remedy was determined using HPLC. The cytotoxic activity against the hepatocarcinoma cell line (HepG2) and cholangiocarcinoma cell line (KKU-M156), in comparison with non-cancerous cell line (HaCaT), were investigated using antiproliferative assay (SRB). The anti-inflammatory activity measured by TNF-α production in RAW 264.7 was determined using ELISA. Results All crude extracts and isolated compounds exhibited significant differences from vincristine sulfate (****p < 0.0001) in their cytotoxic activity against HepG2, KKU-M156, and HaCaT. The PSD remedy exhibited cytotoxic activity against HepG2 and KKU-M156 with IC50 values of 10.45 ± 1.98 (SI = 5.3) and 4.53 ± 0.74 (SI = 12.2) µg/mL, respectively. Some constituents from C. sappan, D. cochinchinensis, M. siamensis, and M. fragrans also exhibited cytotoxic activity against HepG2 and KKU-M156, with IC50 values less than 10 µg/mL. The isolated compounds, i.e., Loureirin B (1), 4-Hydroxy-2,4’-dimethoxydihydrochalcone (2), and Eucomol (3) exhibited moderate cytotoxicity against two cancer cell lines. None of the crude extracts and isolated compounds showed cytotoxicity against HaCaT. D. cochinchinensis and PSD remedy exhibited higher anti-inflammatory activity measured as TNF-α production than acetaminophen. Conclusion The findings provide evidence of bioactivity for EtOH extracts of PSD remedy and the isolated compounds of D. Cochinchinensis. The results consistent the use clinical activity and use of PSD remedy as a antipyretic treatment for liver and bile duct cancer patients by Thai traditional practitioners.
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Alrashid MH, Al-Serri A, Alshemmari SH, Geo JA, Al-Bustan SA. Association analysis of genetic variants in the ghrelin and tumor necrosis factor α genes and the risk for non-Hodgkin's lymphoma in Kuwaitis. Cancer Biomark 2021; 32:11-18. [PMID: 34024815 PMCID: PMC8461683 DOI: 10.3233/cbm-200373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND: Non-Hodgkin’s lymphoma (NHL) is the most common hematological malignancy in the world. Many etiologic factors have been implicated in the risk of developing NHL, including genetic susceptibility and obesity. Single-nucleotide polymorphisms (SNPs) in Ghrelin (GHRL), an anti-inflammatory hormone, and tumor necrosis factor α (TNF-α), an inflammatory cytokine, have been independently associated with the risk for obesity and NHL. OBJECTIVE: To investigate the association between SNPs in GHRL and TNF-α and the risk for NHL and obesity in Kuwaitis. METHODS: We recruited 154 Kuwaiti NHL patients and 217 controls. Genotyping was performed for rs1629816 (GHRL promoter region), rs35684 (GHRL 3’ untranslated region), and rs1800629 (TNF-α promoter region). Logistic regression analysis was performed to assess the association of the investigated SNPs with NHL and the relationship between the selected SNPs with BMI in each group separately. RESULTS: We show that rs1629816 GG was associated with an increased risk for NHL in our sample (p= 0.0003, OR 1.82; CI: 1.31–2.54). None of the investigated SNPs were associated with obesity, nor was obesity found to be associated with the risk for NHL. CONCLUSIONS: Our study demonstrates an association between rs1629816, a SNP in the GHRL regulatory region, and NHL in Kuwaitis.
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Affiliation(s)
- Maryam H Alrashid
- Department of Biological Sciences, Faculty of Science, Kuwait University, Safat, Kuwait
| | - Ahmad Al-Serri
- Department of Pathology, Unit of Human Genetics, Faculty of Medicine, Kuwait University, Safat, Kuwait
| | - Salem H Alshemmari
- Department of Medicine, Faculty of Medicine, Kuwait University, Safat, Kuwait.,Kuwait Cancer Control Center, Kuwait City, Kuwait
| | - Jeethu Anu Geo
- Department of Biological Sciences, Faculty of Science, Kuwait University, Safat, Kuwait
| | - Suzanne A Al-Bustan
- Department of Biological Sciences, Faculty of Science, Kuwait University, Safat, Kuwait
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Wungu CDK, Ariyanto FC, Prabowo GI, Soetjipto, Handajani R. Association between five types of Tumor Necrosis Factor-α gene polymorphism and hepatocellular carcinoma risk: a meta-analysis. BMC Cancer 2020; 20:1134. [PMID: 33228594 PMCID: PMC7686711 DOI: 10.1186/s12885-020-07606-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 10/31/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Research focusing on the relationship between five types of tumor necrosis factor-alpha (TNF-α) SNPs and the risk of hepatocellular carcinoma (HCC) were still controversial. Hereby, we performed a meta-analysis to determine the association between TNF-α promoter SNPs: -1031 T/C, - 863 C/A, - 857 C/T, - 308 G/A, and - 238 G/A with HCC risk. METHODS We interrogated articles from journal database: PubMed, Pro-Quest, EBSCO, Science Direct, and Springer to determine the relationship between five types of SNPs in TNF-α gene with HCC risk. RevMan 5.3 software was used for analysis in fixed/random effect models. RESULTS This meta-analysis included 23 potential articles from 2004 to 2018 with 3237 HCC cases and 4843 controls. We found that SNP - 863 C/A were associated with a significantly increased HCC risk (A vs C, OR = 1.31, 95% CI = 1.03-1.67). Similar results were obtained in - 857 C/T (TT/CT vs CC, OR = 1.31, 95% CI = 1.06-1.62), - 308 G/A (AA vs GG, OR = 3.14, 95% CI = 2.06-4.79), and - 238 G/A (AA vs GG, OR = 3.87, 95% CI = 1.32-11.34). While no associations were observed between SNP TNF-α - 1031 T/C and HCC risk. CONCLUSIONS The present meta-analysis showed that TNFα SNPs -863C/A, - 857 C/T, - 308 G/A, and - 238 G/A were associated with the risk of HCC.
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Affiliation(s)
- Citrawati Dyah Kencono Wungu
- Department of Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia. .,Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.
| | - Fis Citra Ariyanto
- Faculty of Nursing, Universitas Jember, Jember, Indonesia.,Hearing Vision Ltd-Darmo General Hospital, Surabaya, Indonesia
| | - Gwenny Ichsan Prabowo
- Department of Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Soetjipto
- Department of Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.,Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Retno Handajani
- Department of Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.,Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
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Yue X, Jiang X, Zou H, Li G, Wang J, Liu Y. Association of hepatocellular carcinoma risk with polymorphisms in tumour necrosis factor alpha gene in a Chinese Han population. Int J Immunogenet 2020; 47:286-293. [PMID: 31943768 DOI: 10.1111/iji.12474] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 12/06/2019] [Accepted: 12/21/2019] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Studies have shown that the tumour necrosis factor alpha (TNF-α) plays an important role in the development of HCC; however, the association between genetic variations of TNF-α and HCC is not yet fully understood. To evaluate the correlation of TNF-α polymorphisms with HCC, we randomly selected 327 HCC patients and 432 healthy controls, all these subjects reported Han nationality. Genotyping of four TNF-α SNPs (rs1799724, rs1800629, rs1799964 and rs1800610) was performed using the matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) method. Distributions of rs1799964 genotypes and rs1800610 alleles were found to be significantly different between cases and controls (p = .011, p = .001). The recessive model of rs1799964 significantly increased HCC risk (p = .0015), while the dominant and over-dominant models of rs1800610 significantly reduced HCC risk (p = .0096, p = .014). Haplotype analysis of the four TNF-α SNPs revealed that the TGTA haplotype was associated with a reduced HCC risk (p = .0033, OR = 0.53), while the TGTG haplotype was associated with an increased HCC risk (p = .0032, OR = 9.69). These findings indicated that specific TNF-α polymorphisms may be associated with the susceptibility to HCC.
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Affiliation(s)
- Xin Yue
- Department of Radiology, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Xin Jiang
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China
| | - Hongjiu Zou
- Changchun International Travel Healthcare Center, Changchun, China
| | - Gaokai Li
- Department of Toxicology, School of Public Health, Jilin University, Changchun, China
| | - Jinan Wang
- Department of Radiology, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Ying Liu
- Department of Toxicology, School of Public Health, Jilin University, Changchun, China
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Mani MS, Kabekkodu SP, Joshi MB, Dsouza HS. Ecogenetics of lead toxicity and its influence on risk assessment. Hum Exp Toxicol 2019; 38:1031-1059. [PMID: 31117811 DOI: 10.1177/0960327119851253] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
Lead (Pb) toxicity is a public health problem affecting millions worldwide. Advances in 'omic' technology have paved the way to toxico-genomics which is currently revolutionizing the understanding of interindividual variations in susceptibility to Pb toxicity and its functional consequences to exposure. Our objective was to identify, comprehensively analyze, and curate all the potential genetic and epigenetic biomarkers studied to date in relation to Pb toxicity and its association with diseases. We screened a volume of research articles that focused on Pb toxicity and its association with genetic and epigenetic signatures in the perspective of occupational and environmental Pb exposure. Due to wide variations in population size, ethnicity, age-groups, and source of exposure in different studies, researchers continue to be skeptical on the topic of the influence of genetic variations in Pb toxicity. However, surface knowledge of the underlying genetic factors will aid in elucidating the mechanism of action of Pb. Moreover, in recent years, the application of epigenetics in Pb toxicity has become a promising area in toxicology to understand the influence of epigenetic mechanisms such as DNA methylation, chromatin remodeling, and small RNAs for the regulation of genes in response to Pb exposure during early life. Growing evidences of ecogenetic understanding (both genetic and epigenetic processes) in a dose-dependent manner may help uncover the mechanism of action of Pb and in the identification of susceptible groups. Such studies will further help in refining uncertainty factors and in addressing risk assessment of Pb poisoning.
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Affiliation(s)
- M S Mani
- 1 Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - S P Kabekkodu
- 2 Department of Cellular and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - M B Joshi
- 3 Department of Ageing, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - H S Dsouza
- 1 Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Silva PCV, Gomes AV, de Britto LRPB, de Lima ELS, da Silva JL, Montenegro SML, Muniz MTC, Domingues ALC. Influence of a TNF-α Polymorphism on the Severity of Schistosomiasis Periportal Fibrosis in the Northeast of Brazil. Genet Test Mol Biomarkers 2017; 21:658-662. [PMID: 29087736 DOI: 10.1089/gtmb.2017.0133] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIMS The proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) is an essential component in the host immune response to infection, and it has been reported to be an important mediator in severe periportal fibrosis (PPF). We hypothesized that the (-G308A) polymorphism of the TNF-α gene is associated with the severity of PPF and that these polymorphisms influence TNF-α expression. METHODS In this cross-sectional study, we genotyped these polymorphisms within the TNF-α gene in 256 Brazilian subjects infected with Schistosoma mansoni, with different patterns of PPF. RESULTS The genotype (-308) AA was associated with a significant increase in the risk to advanced PPF (OR = 4.60; p = 0.009). In addition, median levels of TNF-α were higher in patients with moderate to advanced PPF, compared with mild fibrosis (20 and 17.3 pg/mL, respectively; p = 0.040). There was no association between average serum levels of TNF-α and (-G308A) TNF-α polymorphism. CONCLUSIONS Our results suggest the (-308) AA genotype may be a risk factor for severity in advanced PPF, in this Brazilian population, and could potentially be used to predict the severity of advanced PPF in schistosomiasis.
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Affiliation(s)
- Paula Carolina Valença Silva
- 1 Departamento de Enfermagem, Universidade Federal de Pernambuco (UFPE) , Vitória de Santo Antão, Pernambuco, Brazil .,2 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil
| | - Adriana Vieira Gomes
- 2 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil .,3 Instituto de Ciências Biológicas, Universidade de Pernambuco (UPE) , Recife, Brazil
| | - Lidiane Régia Pereira Braga de Britto
- 2 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil .,4 Departamento de Fisioterapia, Universidade de Pernambuco (UPE) , Petrolina, Brazil
| | - Elker Lene Santos de Lima
- 2 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil
| | - Jamile Luciana da Silva
- 1 Departamento de Enfermagem, Universidade Federal de Pernambuco (UFPE) , Vitória de Santo Antão, Pernambuco, Brazil
| | | | - Maria Tereza Cartaxo Muniz
- 2 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil .,3 Instituto de Ciências Biológicas, Universidade de Pernambuco (UPE) , Recife, Brazil
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Bader El Din NG, Farouk S, El-Shenawy R, Elhady MM, Ibrahim MK, Dawood RM, Salem AM, El Awady MK. The Synergistic Effect of TNFα -308 G/A and TGFβ1 -509 C/T Polymorphisms on Hepatic Fibrosis Progression in Hepatitis C Virus Genotype 4 Patients. Viral Immunol 2017; 30:127-135. [PMID: 28151059 DOI: 10.1089/vim.2016.0083] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Tumor necrosis factor-alpha (TNFα) and transforming growth factor-beta (TGFβ1) cytokines are highly implicated in liver fibrosis. Polymorphisms in these cytokines affect their expression, secretion, and activity. This study aimed to evaluate the influence of TNFα -308 G/A and TGFβ1 -509 C/T polymorphism on hepatic fibrosis progression in Egyptian patients with hepatitis C virus (HCV) genotype 4. Genotyping of TNFα -308 G/A and TGFβ1 -509 C/T was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 122 subjects (50 healthy controls and 72 HCV patients). Also, serum TNFα and TGFβ1 levels were detected by enzyme-linked immunosorbent assay (ELISA). The genotyping results of early (F0-F1, n = 36) and late (F2-F4, n = 36) HCV fibrosis patients showed that late fibrosis patients had higher TNFα -308 AA genotype and TGFβ1 -509 TT genotype than early fibrosis patients (p = 0.016, 0.028, respectively). Moreover, the TNFα and TGFβ1 serum levels were significantly higher in HCV patients with TNFα A containing genotypes (GA+AA) (p = 0.004) and patients with TGFβ1 T containing genotypes (CT+TT) (p = 0.001), respectively. The combined unfavorable TNFα (GA/AA) and TGFβ1 (CT/TT) genotypes were highly associated with abnormal liver function parameters and were significantly higher in high activity (A2-A3) and late fibrosis (F2-F4) HCV patients (p = 0.023, 0.029). The multivariate analysis results confirmed that the combined TNFα-308 (AA) and TGFβ1 -509 (TT) unfavorable genotypes increased the risk of hepatic fibrosis progression by 6.4-fold than combined favorable genotypes (odds ratio: 6.417, 95% confidence interval [1.490-27.641], p = 0.013). In conclusion, both TNFα -308 G/A and TGFβ1 -509 C/T polymorphisms synergistically influence the hepatic fibrosis progression and can be used as potential biomarkers to predict hepatic disease progression in chronic hepatitis C patients.
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Affiliation(s)
- Noha G Bader El Din
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Sally Farouk
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Reem El-Shenawy
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Mostafa M Elhady
- 2 Department of Biochemistry, Faculty of Science, Ain Shams University , Cairo, Egypt
| | - Marwa K Ibrahim
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Reham M Dawood
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Ahmed M Salem
- 2 Department of Biochemistry, Faculty of Science, Ain Shams University , Cairo, Egypt
| | - Mostafa K El Awady
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
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Luo M, Yang Y, Luo D, Liu L, Zhang Y, Xiao F, Yang J, Zhang C, Fu S, Luo Z. Tumor necrosis factor-alpha promoter polymorphism 308 G/A is not significantly associated with esophageal cancer risk: a meta-analysis. Oncotarget 2016; 7:79901-79913. [PMID: 27821804 PMCID: PMC5346759 DOI: 10.18632/oncotarget.13093] [Citation(s) in RCA: 11] [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: 06/06/2016] [Accepted: 10/21/2016] [Indexed: 12/18/2022] Open
Abstract
Many studies have investigated the association between Tumor necrosis factor-α-308 G>A (rs1800629) and the risk of esophageal cancer. However, their results are inconsistent. Therefore, we performed a meta-analysis of available data to investigate any possible association between this polymorphism and esophageal cancer risk. We searched PubMed, EMBASE, Web of Science, and the CNKI database for articles published up to 2016. Crude and adjusted odds ratio with 95% confidence intervals were calculated using fixed or random effects models. We used a dominant model (GA+AA vs GG), a recessive model (AA vs GG+GA), an over-dominant model (GG+AA vs GA), and allele frequency (G vs A) to identify any association. Eleven studies with 5617 participants were included in the meta-analysis. Our results suggest that TNF-α-308 G>A (rs1800629) is not significantly associated with a risk of esophageal squamous cell carcinoma and esophageal adenocarcinoma. For genetic association studies, negative results of meta-analysis have a high level of evidence, and these results are important in this era of high-throughput sequencing-based precision medicine.
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Affiliation(s)
- Ming Luo
- Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Yuan Yang
- School of Life Sciences, Fudan University, Shanghai, China
| | - Dongmei Luo
- School of Mathematics and Physics, Anhui University of technology, Maanshan, Anhui, China
| | - Liang Liu
- Department of Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Yuening Zhang
- Medical Scientific Research Center, Guangxi Medical University, Nanning, Guangxi, China
| | - Feifan Xiao
- Medical Scientific Research Center, Guangxi Medical University, Nanning, Guangxi, China
| | - Jingcheng Yang
- School of Life Sciences, Fudan University, Shanghai, China
| | - Chengdong Zhang
- Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
- School of Life Sciences, Fudan University, Shanghai, China
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shen Fu
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhiguo Luo
- Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
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Bader El Din NG, Farouk S, El-Shenawy R, Ibrahim MK, Dawood RM, Elhady MM, Salem AM, Zayed N, Khairy A, El Awady MK. Tumor necrosis factor-α -G308A polymorphism is associated with liver pathological changes in hepatitis C virus patients. World J Gastroenterol 2016; 22:7767-7777. [PMID: 27678360 PMCID: PMC5016377 DOI: 10.3748/wjg.v22.i34.7767] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Revised: 07/05/2016] [Accepted: 07/31/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association of tumor necrosis factor alpha (TNFα) -G308A polymorphism with different liver pathological changes in treatment-naïve Egyptian patients infected with hepatitis C virus (HCV) genotype 4. METHODS This study included 180 subjects, composed of 120 treatment-naïve chronic HCV patients with different fibrosis grades (F0-F4) and 60 healthy controls. The TNFα -G308A region was amplified by PCR and the different genotypes were detected by restriction fragment length polymorphism analysis. The TNFα protein was detected by enzyme-linked immunosorbent assay. The influence of different TNFα -G308A genotypes on TNFα expression and liver disease progression were statistically analyzed. The OR and 95%CI were calculated to assess the relative risk confidence. RESULTS Current data showed that the TNFα -G308A SNP frequency was significantly different between controls and HCV infected patients (P = 0.001). Both the AA genotype and A allele were significantly higher in late fibrosis patients (F2-F4, n = 60) than in early fibrosis patients (F0-F1, n = 60) (P = 0.05, 0.04 respectively). Moreover, the GA or AA genotypes increased the TNFα serum level greater than the GG genotype (P = 0.002). The results showed a clear association between severe liver pathological conditions (inflammation, steatosis and fibrosis) and (GA + AA) genotypes (P = 0.035, 0.03, 0.04 respectively). The stepwise logistic regression analysis showed that the TNFα genotypes (GA + AA) were significantly associated with liver inflammation (OR = 3.776, 95%CI: 1.399-10.194, P = 0.009), severe steatosis (OR = 4.49, 95%CI: 1.441-14.0, P = 0.010) and fibrosis progression (OR = 2.84, 95%CI: 1.080-7.472, P = 0.034). Also, the A allele was an independent risk factor for liver inflammation (P = 0.003), steatosis (P = 0.003) and fibrosis (P = 0.014). CONCLUSION TNFα SNP at nucleotide -308 represents an important genetic marker that can be used for the prognosis of different liver pathological changes in HCV infected patients.
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Banday MZ, Balkhi HM, Hamid Z, Sameer AS, Chowdri NA, Haq E. Tumor necrosis factor-α (TNF-α)-308G/A promoter polymorphism in colorectal cancer in ethnic Kashmiri population - A case control study in a detailed perspective. Meta Gene 2016; 9:128-36. [PMID: 27331018 PMCID: PMC4908285 DOI: 10.1016/j.mgene.2016.06.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 06/01/2016] [Indexed: 12/31/2022] Open
Abstract
Background Inflammation constitutes one of the important components of colorectal cancer (CRC) pathogenesis. Tumor necrosis factor-α (TNF-α), a cytokine and an important inflammatory mediator plays a pivotal role in the malignant cellular proliferation, angiogenesis, tissue invasion and metastasis in CRC. The studies on association of various polymorphisms in human TNF-α gene including TNF-α-308G/A single nucleotide polymorphism (SNP) are limited, mixed and inconclusive. Materials and methods The aim of this study was to analyze the association of TNF-α-308G/A promoter SNP with colorectal cancer (CRC) susceptibility and development risk and also to evaluate the modifying effects of possible TNF-α-308G/A genotypes on different risk factors of CRC in ethnic population of Kashmir, India through a case–control setup. The genotype frequencies of TNF-α-308G/A promoter SNP were compared between 142 CRC patients and 184 individually matched healthy controls by using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. The associations between the TNF-α-308G/A SNP and CRC risk were examined through conditional logistic regression models adjusted for multiple possible confounding (third) variables. Further, the associations between this SNP and various clinico-pathological parameters, demographic variables and environmental factors within the case group subjects with regard to CRC risk were also evaluated. Results The association between the TNF-α-308G/A SNP and the modulation of risk of CRC was not found to be significant (p value = 0.156). The effect of less common TNF-α-308A allele on the risk of colorectal cancer was also not found to be significant (p value = 0.175). The variant genotype (AA) was nonexistent in the study population. Further, we found no significant effect modulation of CRC risk by wild and heterozygous TNF-α-308G/A SNP genotypes in presence of different possible risk factors (p > 0.05). We also found no significant association of TNF-α-308G/A SNP with the subsets of various characteristics of the case group subjects under study (p > 0.05). Conclusions This study indicates that there is no significant association between the TNF-α-308G/A promoter SNP and the risk of developing CRC in ethnic Kashmiri population. However, in order to substantiate our findings, this study needs to be replicated with bigger sample size and should involve other ethnically defined populations with high CRC risk.
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Affiliation(s)
- Mujeeb Zafar Banday
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India
| | - Henah Mehraj Balkhi
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India
| | - Zeenat Hamid
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India
| | - Aga Syed Sameer
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Nissar A. Chowdri
- Department of Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India
| | - Ehtishamul Haq
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India
- Corresponding author.
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12
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Tavakolpour S, Sali S. Tumor Necrosis Factor-α-308 G/A Polymorphisms and Risk of Hepatocellular Carcinoma: A Meta-Analysis. HEPATITIS MONTHLY 2016; 16:e33537. [PMID: 27257425 PMCID: PMC4888758 DOI: 10.5812/hepatmon.33537] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 03/14/2016] [Indexed: 12/11/2022]
Abstract
CONTEXT Hepatocellular carcinoma (HCC) is a common disorder throughout the world that can develop due to various factors, including genetics. Tumor necrosis factor-α (TNF-α) is the most frequently studied cytokine related to the risk of developing HCC, and an association between the 308 position of the TNF-α promoter (TNF-α-308) and HCC risk has been confirmed in various reports. EVIDENCE ACQUISITION The PubMed, Scopus, and Google Scholar databases were searched through July 12, 2015, for studies on associations between TNF-α-308 and the risk of HCC. To determine this association, odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS A total of 23 case-control studies were investigated, involving 3,389 cases and 4,235 controls. The overall conclusion was that the A allele was more frequent in case groups compared to control groups (13.4% vs. 8.4%). Thus, the A allele was significantly associated with increased HCC risk (OR = 1.77; 95% CI = [1.26-2.50]; P value < 0.002). In addition to the allelic model, the dominant model (AA + AG vs. GG) was significantly associated with HCC risk (OR = 1.80; CI = [1.29-2.51]; P value < 0.001). In the sensitivity analysis for co-dominant (AA vs. GG) and recessive models (AA vs. AG + GG), no trustworthy associations with the risk of HCC development were observed. CONCLUSIONS This meta-analysis indicated that the TNF-α-308 G/A polymorphism is significantly associated with increased susceptibility to HCC. However, to confirm this finding, more studies are needed on TNF-α-308 G/A polymorphisms associated with HCC.
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Affiliation(s)
- Soheil Tavakolpour
- Iran University of Medical Sciences, Tehran, IR Iran
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Shahnaz Sali
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
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13
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Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 2016. [PMID: 26819510 DOI: 10.3748/wjg.v22.i4.141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.
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Affiliation(s)
- Ignacio Novo-Veleiro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Lucía Alvela-Suárez
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Antonio-Javier Chamorro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Rogelio González-Sarmiento
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Francisco-Javier Laso
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Miguel Marcos
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
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14
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Sun Q, Guo X, Wang Q, Zhao F. The association of TNF-308 (G/A) gene polymorphisms and hepatocellular carcinoma risk: a meta-analysis. Chin J Cancer Res 2016; 28:536-542. [PMID: 27877013 PMCID: PMC5101228 DOI: 10.21147/j.issn.1000-9604.2016.05.09] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective Many studies have examined the association between the TNF-308 G/A polymorphism gene polymorphisms and hepatocellular carcinoma risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, a meta-analysis was performed. Methods The PubMed and CNKI (China National Knowledge Infrastructure) database was searched for case-control studies. Odds ratios (OR) with 95% CIs were used to determine the strength of association between the TNF-308 G/A polymorphisms and HCC risk. The pooled ORs for the risk associated with the TNF-308 G/A genotype, the A carriers (A/G + A/A) vs. the wild-type homozygotes (G/G), A/A vs. G/G were calculated, respectively. Subgroup analyses were done by ethnicity and smoking status. Heterogeneity assumptions were assessed by chi-square-based Q-test. Results Ultimately, 21 studies, comprising 2,923 hepatocellular carcinoma cases and 4,323 controls were included. Overall, the A carriers (G/A + A/A) vs. the wild-type homozygotes (G/G), the pooled OR was 1.05 (95% CI, 0.93-1.19; P=0.000 for heterogeneity), for A/A vs. G/G the pooled OR was 1.07 (95% CI, 0.95-1.21; P=0.007 for heterogeneity). In the stratified analysis by ethnicity, the significantly risks were found among non-Asians. However, for Asians, significantly risks were not found. Conclusions The TNF-308 G/A polymorphisms are not associated with hepatocellular carcinoma risk among Asians, but for non-Asians.
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Affiliation(s)
- Qing Sun
- Department of Oncology, Wuxi 2nd People's Hospital, Affiliated to Nanjing Medical University, Wuxi 214002, China
| | - Xuedan Guo
- Department of Oncology, Wuxi 2nd People's Hospital, Affiliated to Nanjing Medical University, Wuxi 214002, China
| | - Qi Wang
- Department of Oncology, Wuxi 2nd People's Hospital, Affiliated to Nanjing Medical University, Wuxi 214002, China
| | - Fan Zhao
- Department of Oncology, Wuxi 2nd People's Hospital, Affiliated to Nanjing Medical University, Wuxi 214002, China
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15
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Heidor R, de Conti A, Ortega JF, Furtado KS, Silva RC, Tavares PELM, Purgatto E, Ract JNR, de Paiva SAR, Gioielli LA, Pogribny IP, Moreno FS. The chemopreventive activity of butyrate-containing structured lipids in experimental rat hepatocarcinogenesis. Mol Nutr Food Res 2015; 60:420-9. [PMID: 26548572 DOI: 10.1002/mnfr.201500643] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 10/15/2015] [Accepted: 10/26/2015] [Indexed: 12/26/2022]
Abstract
SCOPE Emerging evidence indicates that the use of bioactive food components is a promising strategy to prevent the development of liver cancer. The goal of this study was to examine the chemopreventive effect of butyrate-containing structured lipids (STLs) produced by an enzymatic interesterification of tributyrin and flaxseed oil on rat hepatocarcinogenesis. METHODS AND RESULTS Male Wistar rats were subjected to a classic "resistant hepatocyte" model of liver carcinogenesis and treated with STLs, tributyrin or flaxseed oil during the initial phases of hepatocarcinogenesis. Treatment with STLs and tributyrin strongly inhibited the development of preneoplastic liver lesions. The chemopreventive activity of tributyrin was associated with the induction of apoptosis and reduction of the expression of major activated hepatocarcinogenesis-related oncogenes. Treatment with STLs caused substantially greater inhibitory effects than tributyrin on oncogene expression. CONCLUSION These results demonstrate that the tumor-suppressing activity of butyrate-containing STLs is associated with its ability to prevent and inhibit activation of major hepatocarcinogenesis-related oncogenes. Enrichment of histone H3K9me3 and H3K27me3 at the promoter of Myc and Ccnd1 genes may be related to the inhibitory effect on oncogene expression in the livers of STL-treated rats.
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Affiliation(s)
- Renato Heidor
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.,Advanced Research Center in Food Science and Nutrition (NAPAN), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.,Food Research Center (FORC), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil
| | - Aline de Conti
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, USA
| | - Juliana F Ortega
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Kelly S Furtado
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.,Advanced Research Center in Food Science and Nutrition (NAPAN), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil
| | - Roberta C Silva
- Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Paulo E L M Tavares
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Eduardo Purgatto
- Laboratory of Food Chemistry and Biochemistry, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.,Advanced Research Center in Food Science and Nutrition (NAPAN), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.,Food Research Center (FORC), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil
| | - Juliana N R Ract
- Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Sérgio A R de Paiva
- Department of Internal Medicine, Botucatu Medical School, UNESP - São Paulo State University, Botucatu, Brazil.,Food Research Center (FORC), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil
| | - Luiz A Gioielli
- Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Igor P Pogribny
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, USA
| | - Fernando S Moreno
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.,Advanced Research Center in Food Science and Nutrition (NAPAN), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.,Food Research Center (FORC), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil
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16
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Oliveira JB, Silva PCV, Vasconcelos LM, Gomes AV, Coêlho MRCD, Cahu GGOM, Muniz MTC, Domingues ALC. Influence of Polymorphism (-G308A) TNF-α on the Periportal Fibrosis Regression of Schistosomiasis After Specific Treatment. Genet Test Mol Biomarkers 2015; 19:598-603. [PMID: 26406299 DOI: 10.1089/gtmb.2015.0091] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AIMS Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine and important mediator of severity for periportal fibrosis (PPF). We hypothesized that the (-G380A) polymorphism in the TNF-α gene is associated with regression of PPF after treatment for schistosomiasis mansoni. METHODS This is a retrospective cohort study, involving 124 Brazilian patients infected with Schistosoma mansoni, who were followed for 2 years after treatment to estimate the likelihood of PPF regression. Sociodemographic and clinical factors were also identified, with emphasis on specific treatment. RESULTS No statistical difference was observed between sociodemographic and clinical factors among the exposed groups. Genotypes (-308) GA/AA were positively associated with the degree of PFF regression (relative risk [RR] = 0.52; ρ = 0.025), as well as in the image pattern of PPF (RR = 0.56; ρ = 0.048), when compared with the genotype (-308) GG. There was no statistical difference in TNF-α serum levels between the exposed groups. CONCLUSIONS These results suggest that the (-G308A) polymorphism of the TNF-α gene may be one of the factors that prevents the regression of the degree and pattern of PPF in the Brazilian population, and thus it may potentially be a predictive factor of PPF intensity in schistosomiasis.
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Affiliation(s)
- Juliana B Oliveira
- 1 Gastroenterologia, Hospital das Clínicas , Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Paula C V Silva
- 2 Centro Acadêmico de Vitória, Universidade Federal de Pernambuco , Vitória de Santo Antão, Pernambuco, Brazil .,3 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil
| | - Leticia M Vasconcelos
- 2 Centro Acadêmico de Vitória, Universidade Federal de Pernambuco , Vitória de Santo Antão, Pernambuco, Brazil
| | - Adriana V Gomes
- 3 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil .,4 Instituto de Ciências Biológicas, Universidade de Pernambuco , Recife, Pernambuco, Brazil
| | - Maria Rosãngela C D Coêlho
- 5 Setor de Virologia do Laboratório de Imunopatologia Keizo-Asami (LIKA), Universidade Federal de Pernambuco , Recife, Pernambuco, Brazil .,6 Departamento de Fisiologia e Farmacologia, Universidade Federal de Pernambuco , Recife, Pernambuco, Brazil
| | - Georgea G O M Cahu
- 5 Setor de Virologia do Laboratório de Imunopatologia Keizo-Asami (LIKA), Universidade Federal de Pernambuco , Recife, Pernambuco, Brazil
| | - Maria Tereza Cartaxo Muniz
- 3 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil .,4 Instituto de Ciências Biológicas, Universidade de Pernambuco , Recife, Pernambuco, Brazil .,7 Faculdade de Ciências Médicas, Universidade de Pernambuco , Recife, Pernambuco, Brazil
| | - Ana Lúcia C Domingues
- 8 Departamento de Medicina Clínica, Universidade Federal de Pernambuco , Recife, Pernambuco, Brazil
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Tumour Necrosis Factor-α Gene Polymorphism Is Associated with Metastasis in Patients with Triple Negative Breast Cancer. Sci Rep 2015; 5:10244. [PMID: 26165253 PMCID: PMC4499887 DOI: 10.1038/srep10244] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 04/07/2015] [Indexed: 12/31/2022] Open
Abstract
Tumour necrosis factor-α (TNF-α) is critical in the regulation of inflammation and tumour progression. TNF-α-308G > A is associated with constitutively elevated TNF-α expression. The purpose of this study was to assess the association between TNF-α-308G > A and breast cancer (BC) risk by subtype and the connection between genotypes and clinical features of BC. A total of 768 patients and 565 controls were enrolled in this study, and genotypes were detected using the TaqMan assay. No effect on susceptibility for any BC subtype was found for the TNF-α-308 polymorphism in our study or in the pooled meta-analysis. This polymorphism was shown to be associated with age at menarche in all BC and in progesterone receptor-negative BC. Interestingly, triple negative breast cancer (TNBC) patients with TNF-α-308A had an increased risk of distant tumour metastasis (OR = 3.80, 95% CI: 1.31-11.02, P = 0.009). Multi-regression analysis showed that TNF-α-308A was also a risk factor for distant tumour metastasis after adjustment for tumour size and lymph node metastasis status (OR = 6.26, 95% CI: 1.88-20.87, P = 0.003). These findings indicate that TNF-α might play a distinct role in the progression of TNBC, especially in distant tumour metastasis of TNBC.
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18
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Wang F, Chen S, Xu R. WITHDRAWN: Association of TNF-α-308G>A polymorphisms with hepatocellular carcinoma in Han Chinese population: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2014:S2210-7401(14)00251-4. [PMID: 25497275 DOI: 10.1016/j.clinre.2014.10.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 09/25/2014] [Accepted: 10/14/2014] [Indexed: 02/04/2023]
Abstract
The Editor and Publisher of "Clinics and Research in Hepatology and Gastroenterology" have decided to withdraw this article because they consider that it has been accepted based upon the positive advice of at least one faked reviewer report. This manipulation of the peer-review process represents a clear violation of the fundamentals of peer review, our publishing policies, and publishing ethics standards. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. The Publisher apologizes for any inconvenience this may cause.
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Affiliation(s)
- Feng Wang
- School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China; Institute of Molecular Medicine and School of Biomedical Science, Huaqiao University, Quanzhou 362021, China.
| | - Siyi Chen
- Nanning Center for Disease Control and Prevention, Nanning 530021, China
| | - Ruian Xu
- Institute of Molecular Medicine and School of Biomedical Science, Huaqiao University, Quanzhou 362021, China.
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19
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Feng H, Kuai JH, Zhang MY, Wang GC, Shi YJ, Zhang JY. Tumor necrosis factor-alpha gene -308G > A polymorphism alters the risk of hepatocellular carcinoma in a Han Chinese population. Diagn Pathol 2014; 9:199. [PMID: 25420786 PMCID: PMC4282739 DOI: 10.1186/s13000-014-0199-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 10/08/2014] [Indexed: 01/13/2023] Open
Abstract
Background The aim of the present study was to evaluate the influence of tumor necrosis factor-alpha (TNF-α) −308 G > A polymorphism on hepatocellular carcinoma (HCC) risk. Methods The present case–control study was conducted in a Han Chinese population consisting of 753 HCC patients and 760 controls from May 2010 to March 2013. The −308 TNF-a promoter polymorphisms were detected. Conditional logistic regression was performed to analyze the association between TNF-α −308 G > A polymorphism and the risk of HCC, which were estimated by odds ratios (ORs) and their 95% confidence intervals (95% CIs). Results The genotypic frequencies in the cases were not similar to that of the controls, differences being statistically significant (P = 0.002). Using the GG genotype as the reference genotype, AA was significantly associated with increased risk of HCC (adjusted OR = 5.12, 95% CI = 2.31–7.82). Similarly, AG + AA genotype showed 5.59-fold increased HCC risk in a dominant model. Furthermore, we found A allele was significantly associated with increased risk of HCC, compared with G allele (OR = 4.18, 95% CI = 1.76–6.97). Conclusion The present study showed that TNF-α −308 G > A polymorphism was associated with increased HCC risk in a Han Chinese population. Further prospective studies on large and different ethnic populations will be necessary to confirm our findings and elucidate the underlying molecular mechanism for the development of HCC. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_199
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Affiliation(s)
- Hua Feng
- Digestive Disease Department, Shandong Provincial Hospital, Affliated to Shandong University, Jinan, Shandong, China.
| | - Jing-hua Kuai
- Digestive Disease Department, Qi Lu Hospital of ShanDong University (QingDao), QingDao, Shandong, China.
| | - Ming-yan Zhang
- Digestive Disease Department, Shandong Provincial Hospital, Affliated to Shandong University, Jinan, Shandong, China.
| | - Guang-chuan Wang
- Digestive Disease Department, Shandong Provincial Hospital, Affliated to Shandong University, Jinan, Shandong, China.
| | - Yong-jun Shi
- Digestive Disease Department, Shandong Provincial Hospital, Affliated to Shandong University, Jinan, Shandong, China.
| | - Jun-yong Zhang
- Digestive Disease Department, Shandong Provincial Hospital, Affliated to Shandong University, Jinan, Shandong, China. .,Degestive Disease Department, Shandong Provincial Hospital, Num 324, JingWu Wei Qi Road, Jinan, PR China.
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20
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Hu Q, Lou GG, Liu YC, Qian L, Lv BD. The Tumor Necrosis Factor-α-308 and -238 Polymorphisms and Risk of Hepatocellular Carcinoma for Asian Populations: A Meta-Analysis. Curr Ther Res Clin Exp 2014; 76:70-5. [PMID: 25352937 PMCID: PMC4209508 DOI: 10.1016/j.curtheres.2014.04.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2014] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Tumor necrosis factor-α (TNF-α) has been suggested to play a very important role in the development and progression of hepatocellular carcinoma (HCC). Many studies have identified the associations of TNF-α-308 and -238 polymorphisms with HCC risk, but the results remain controversial. AIM We conducted this meta-analysis to evaluate the associations between TNF-α-308 and -238 polymorphisms and HCC susceptibility. METHODS PubMed, Embase, and China National Knowledge Infrastructure electronic databases were searched for all articles on associations between TNF-α-308 and -238 polymorphisms and HCC risk in Asians through September 30, 2013. Odds ratios (ORs) and their 95% CIs were calculated to assess the strength of this association. RESULTS A total of 17 case-control studies were identified in our meta-analysis. For the TNF-α-308 G/A polymorphism, 14 studies containing 3154 cases and 3767 controls were included. Overall, the frequency of the A allele was higher in patients with HCC than in the healthy controls (10.2% vs 7.5%), and the A allele and allele carrier were significantly associated with increased risk of HCC in a random effects model (A vs G: OR = 1.57; 95% CI, 1.22-2.01; P = 0.0004; AA + AG vs GG: OR = 1.62; 95% CI, 1.18-2.22; P = 0.003). For the TNF-α-238 polymorphism, 10 research articles were identified. No association was found between the TNF-α-238 G/A polymorphism and risk of HCC in any genetic models (P > 0.05). The sensitivity analysis further strengthened the overall correlations. CONCLUSIONS Our meta-analysis proved that the TNF-α-308 G/A polymorphism is associated with increased susceptibility to HCC. However, the TNF-α-238 G/A polymorphism is not significantly associated with risk of HCC in Asian populations. Further studies with large sample sizes are needed to confirm these associations among other populations.
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Affiliation(s)
- Qing Hu
- The Second Affiliated Hospital, Zhejiang Traditional Chinese Medical University, Hangzhou, China
| | - Guo-Guang Lou
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ying-Chao Liu
- The Second Affiliated Hospital, Zhejiang Traditional Chinese Medical University, Hangzhou, China
| | - Le Qian
- The Second Affiliated Hospital, Zhejiang Traditional Chinese Medical University, Hangzhou, China
| | - Bo-Dong Lv
- The Second Affiliated Hospital, Zhejiang Traditional Chinese Medical University, Hangzhou, China
- Address correspondence to: Bo-Dong Lv, PhD, The Second Affiliated Hospital, University of Zhejiang Traditional Chinese Medicine, 548 Bingwen Rd, Bingjiang District, Hangzhou, 310005, China.
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Association of TNF-α Promoter Polymorphism with HBV Associated Disease Outcome Among HBV Infected Patients from Orissa, Southern Part of East India. J Clin Exp Hepatol 2014; 4:202-8. [PMID: 25755561 PMCID: PMC4284202 DOI: 10.1016/j.jceh.2014.08.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 08/14/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND TNF-α promoter polymorphism has been known to be a potential predictive factor in patients with HBV infection. We therefore tried to investigate whether the TNF-α promoter polymorphism at position -238, -857 and -863 was associated with the outcome of HBV infection in a population from Orissa, southern part of East India. METHODS A total of 195 patients recruited for the study were classified into 85 controls and 110 HBV infected cases, which included 34 IC, 30 CLD, 32 LC and 14 HCC patients. The polymorphisms at the respective sites were detected by a PCR-RFLP followed by statistical analysis. RESULTS The frequency of the genotype -238 GG and the allele -238G in the cases (89.0% and 92.7% respectively) was significantly higher than that in the controls (68.2% and 82.2% respectively) (P < 0.001, OR = 3.8 and P = 0.001, OR = 2.73). Whereas the -238 GA genotype was significantly high in the control group (28.2%) when compared to the cases (7.2%) (P < 0.001, OR = 0.2). Similarly, the frequency of -863CC and the allele -863C was significantly higher among the cases (24.5% and 49.5%) compared to controls (1.17% and 34.7%), (P < 0.001, OR = 27.32 and P = 0.003, OR = 1.85), whereas the -863CA genotype was significantly high in the controls (67.0%) when compared to the cases (50.0%) (P = 0.01, OR = 0.49). Haplotype -863C/-857C/-238G in cases was significantly higher than controls (P = 0.002). Multivariate logistic regression analysis indicates that the genotype -863CC bears a negative association with liver disease progression. CONCLUSION The present study established an association of polymorphisms at site -238 and -863 of the TNF-α promoter with the outcome HBV infection and disease progression.
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Different role of tumor necrosis factor-α polymorphism in non-Hodgkin lymphomas among Caucasian and Asian populations: a meta-analysis. Int J Mol Sci 2014; 15:7684-98. [PMID: 24857911 PMCID: PMC4057699 DOI: 10.3390/ijms15057684] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 04/15/2014] [Accepted: 04/23/2014] [Indexed: 01/26/2023] Open
Abstract
Tumor necrosis factor-α (TNF-α) is an immunoregulatory cytokine involved in B- and T-cell function, and also plays an important role in inflammation and cancer. TNF-α-308G>A has been associated with constitutively elevated TNF-α expression. Several studies have reported the association between the TNF-α-308G>A polymorphism and non-Hodgkin lymphomas (NHL) risk, however, results are still inconsistent. To solve these conflicts, we conducted the first meta-analysis to assess the effect of TNF-α-308G>A polymorphism on the risk of NHL and various subtypes (additive model) including 10,619 cases and 12,977 controls in Caucasian and Asian populations. Our meta-analysis indicated that TNF-α-308G>A polymorphism is not associated with NHL risk when pooling all studies together (OR=1.06, 95% CI: 0.92-1.23, p=0.413). In stratified analyses, we found TNF-α-308A allele was significantly associated with higher risk of NHL, B-cell lymphomas (BCL), T-cell lymphomas (TCL) and diffuse large B-cell lymphomas (DLBCL) in Caucasians (OR=1.22, 95% CI: 1.06-1.40, p=0.007; OR=1.18, 95% CI: 1.03-1.34, p=0.014; OR=1.20, 95% CI: 1.01-1.42, p=0.040; OR=1.21, 95% CI: 1.11-1.32, p<0.001, respectively). Interestingly, it was associated with decreased risk of NHL, BCL and DLBCL in Asians (OR=0.75, 95% CI: 0.66-0.86, p<0.001; OR=0.70, 95% CI: 0.52-0.94, p=0.018; OR=0.70, 95% CI: 0.57-0.86, p=0.001). These findings also suggest TNF-α might play a distinct role in pathogenesis of NHL in different populations.
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Tumour necrosis factor alpha 308 G/A is a risk marker for the progression from high-grade lesions to invasive cervical cancer. Tumour Biol 2013; 35:2561-4. [DOI: 10.1007/s13277-013-1337-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 10/16/2013] [Indexed: 12/14/2022] Open
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Aroucha D, do Carmo R, Moura P, Silva J, Vasconcelos L, Cavalcanti M, Muniz M, Aroucha M, Siqueira E, Cahú G, Pereira L, Coêlho M. High tumor necrosis factor-α/interleukin-10 ratio is associated with hepatocellular carcinoma in patients with chronic hepatitis C. Cytokine 2013; 62:421-5. [DOI: 10.1016/j.cyto.2013.03.024] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Revised: 03/23/2013] [Accepted: 03/23/2013] [Indexed: 12/15/2022]
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Xie L, Liang XN, Deng Y, Qin X, Li S. TNF-α-308G/A polymorphisms and nasopharyngeal cancer risk: a meta-analysis. Eur Arch Otorhinolaryngol 2012. [PMID: 23183825 DOI: 10.1007/s00405-012-2276-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Previous evidence has indicated that the polymorphism of tumor necrosis factor-alpha (TNF-α) is a risk factor for various cancers, however, the association between TNF-α-308G/A polymorphism and nasopharyngeal carcinoma (NPC) remains controversial and ambiguous. The aim of this study is to clarify the association between TNF-α polymorphism and NPC using meta-analysis. A meta-analysis based on five eligible case-control studies involving 499 cases and 1,470 controls was carried out to summarize the data on the association between TNF-α-308G/A polymorphism and NPC risk. Odds ratios (OR) with 95 % confidence intervals (95 % CI) were used to assess the strength of this association in the fixed-effect model. The pooled analyses showed no significant association between TNF-α-308G/A polymorphism and NPC (AA vs. GG: OR = 1.38, P = 0.193; GA vs. GG: OR = 0.92, P = 0.585; GA + AA vs. GG: OR = 1.00, P = 0.972; AA vs. GA + GG: OR = 1.44, P = 0.138). We also categorized by geographic location (non-Asian or Asian) for subgroup analysis; the results also showed no significant association between TNF-α-308G/A polymorphism and NPC risk in all of the comparisons. No publication bias was observed in this study (t = -0.11, P = 0.918, 95 % CI = -4.893-4.559). No significant association was found between TNF-α-308G/A polymorphism and the risk for NPC.
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Affiliation(s)
- Li Xie
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Zhuang Autonomous Region, People's Republic of China
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TNF-α Polymorphisms in Juvenile Idiopathic Arthritis: Which Potential Clinical Implications? Int J Rheumatol 2012; 2012:756291. [PMID: 23133455 PMCID: PMC3485518 DOI: 10.1155/2012/756291] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Revised: 07/13/2012] [Accepted: 08/03/2012] [Indexed: 02/06/2023] Open
Abstract
Whether tumor necrosis factor alpha (TNF-α) gene polymorphisms (SNPs) influence disease susceptibility and treatment of patients with juvenile idiopathic arthritis (JIA) is presently uncertain. TNF-α is one of the most important cytokine involved in JIA pathogenesis. Several single nucleotide polymorphisms (SNPs) have been identified within the region of the TNF-α gene but only a very small minority have proven functional consequences and have been associated with susceptibility to JIA. An association between some TNF-α SNPs and adult rheumatoid arthritis (RA) susceptibility, severity and clinical response to anti-TNF-α treatment has been reported. The most frenquetly studied TNF-α SNP is located at -308 position, where a substitution of the G allele with the rare A allele has been found. The presence of the allele -308A is associated to JIA and to a poor prognosis. Besides, the -308G genotype has been associated with a better response to anti-TNF-α therapy in JIA patients, confirming adult data. Psoriatic and oligoarticular arthritis are significantly associated to the -238 SNP only in some works. Studies considering other SNPs are conflicting and inconclusive. Large scale studies are required to define the contribution of TNF-α gene products to disease pathogenesis and anti-TNF-α therapeutic efficacy in JIA.
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Lalonde ME, Ouimet M, Larivière M, Kritikou EA, Sinnett D. Identification of functional DNA variants in the constitutive promoter region of MDM2. Hum Genomics 2012; 6:15. [PMID: 23244604 PMCID: PMC3500213 DOI: 10.1186/1479-7364-6-15] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Accepted: 05/31/2012] [Indexed: 01/30/2023] Open
Abstract
Although mutations in the oncoprotein murine double minute 2 (MDM2) are rare, MDM2 gene overexpression has been observed in several human tumors. Given that even modest changes in MDM2 levels might influence the p53 tumor suppressor signaling pathway, we postulated that sequence variation in the promoter region of MDM2 could lead to disregulated expression and variation in gene dosage. Two promoters have been reported for MDM2; an internal promoter (P2), which is located near the end of intron 1 and is p53-responsive, and an upstream constitutive promoter (P1), which is p53-independent. Both promoter regions contain DNA variants that could influence the expression levels of MDM2, including the well-studied single nucleotide polymorphism (SNP) SNP309, which is located in the promoter P2; i.e., upstream of exon 2. In this report, we screened the promoter P1 for DNA variants and assessed the functional impact of the corresponding SNPs. Using the dbSNP database and genotyping validation in individuals of European descent, we identified three common SNPs (-1494 G > A; indel 40 bp; and -182 C > G). Three major promoter haplotypes were inferred by using these three promoter SNPs together with rs2279744 (SNP309). Following subcloning into a gene reporter system, we found that two of the haplotypes significantly influenced MDM2 promoter activity in a haplotype-specific manner. Site-directed mutagenesis experiments indicated that the 40 bp insertion/deletion variation is causing the observed allelic promoter activity. This study suggests that part of the variability in the MDM2 expression levels could be explained by allelic p53-independent P1 promoter activity.
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Affiliation(s)
- Marie-Eve Lalonde
- Division of Hematology-Oncology, Research Center, Sainte-Justine Hospital, 3175 Chemin de la Cote-Sainte-Catherine, Montreal H3T 1C5, Canada
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Lee JH, Chung YH, Kim JA, Shim JH, Lee D, Lee HC, Shin ES, Yoon JH, Kim BI, Bae SH, Koh KC, Park NH. Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma. Cancer 2012; 119:136-42. [PMID: 22736425 DOI: 10.1002/cncr.27705] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 04/04/2012] [Accepted: 05/14/2012] [Indexed: 12/16/2022]
Abstract
BACKGROUND Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand-foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib-induced HFSR and genetic polymorphisms in Korean patients with HCC. METHODS For this prospective cohort study, the authors enrolled 59 consecutive patients with intermediate stage HCC from 5 centers in Korea. All patients received sorafenib 400 mg twice daily in combination with transarterial chemoembolization (TACE). Genotyping was performed on a total of 49 single nucleotide polymorphisms (SNPs) in 8 candidate genes (minor allelic frequency ≥5%). Serum levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) were measured using enzyme-linked immunosorbent assays before therapy and 1 month after therapy. RESULTS During a median treatment period of 18 months, 55 patients (93%) developed sorafenib-induced HFSR, including grade 1 reactions in 15 patients, grade 2 reactions in 27 patients, and grade 3 reaction in 13 patients. The SNPs TNF-α -308GG, VEGF -94GG, VEGF 1991CC, VEGF IVS3-28CC, and uridine diphosphate glucuronosyltransferase 1 family-polypeptide A9 (UGT1A9) IVS1-37431AA were associated significantly with the development of high-grade (grade 2 or 3) HFSR in univariate analysis (P < .05). In multivariate analysis, the SNPs VEGF 1991CC (odds ratio, 45.7), TNF-α -308GG (odds ratio, 44.1), and UGT1A9 IVS1-37431AA (odds ratio, 18.7) were identified as independent risk factors for the development of high-grade HFSR (P = .01, P = .02, and P = .02, respectively). He serum TNF-α level measured 1 month after sorafenib therapy was correlated significantly with the development of high-grade HFSR (odds ratio, 3.56; P = .026). CONCLUSIONS Differences in the incidence of HFSR may have been caused by ethnic differences in genetic polymorphisms of the TNF-α, VEGF, and UGT1A9 genes, especially in relation to the expression of serum TNF-α after sorafenib therapy.
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Affiliation(s)
- Joo Ho Lee
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
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Radwan MI, Pasha HF, Mohamed RH, Hussien HIM, El-Khshab MN. Influence of transforming growth factor-β1 and tumor necrosis factor-α genes polymorphisms on the development of cirrhosis and hepatocellular carcinoma in chronic hepatitis C patients. Cytokine 2012; 60:271-6. [PMID: 22682513 DOI: 10.1016/j.cyto.2012.05.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 05/13/2012] [Accepted: 05/14/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Host genetic factors may affect clinical outcomes of hepatitis C virus (HCV) infection; however, the possible mechanisms remain largely unknown. This study aimed to evaluate transforming growth factor-β1 (TGF-β1)-509 and tumor necrosis factor-α (TNF-α)-308 genes polymorphisms as a risk factors for cirrhosis and hepatocellular carcinoma (HCC) in chronic hepatitis C patients. MATERIALS AND METHODS Two hundred and eighty HCV patients (152 patients with cirrhosis, 128 patients with HCC) and 160 controls were enrolled in the study. Polymorphisms of TGF-β1-509 and TNF-α-308 gene were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum TGF-β1 and TNF-α were determined using ELISA. RESULTS TGF-β1-509 TT, TNF-α-308 AA and GA genotypes frequencies were significantly increased in cirrhotic and HCC groups. Serum TGF-β1 and TNF-α level were significantly increased in TGF-β1-509 TT and TNF-α-308 AA genotypes respectively. CONCLUSION TGF-β1-509 and TNF-α-308 genes polymorphisms are associated with risk of liver cirrhosis and HCC in patients with chronic HCV infection.
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Affiliation(s)
- Mohamed I Radwan
- Tropical Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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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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Talaat RM, Esmail AA, Elwakil R, Gurgis AA, Nasr MI. Tumor necrosis factor-alpha -308G/A polymorphism and risk of hepatocellular carcinoma in hepatitis C virus-infected patients. CHINESE JOURNAL OF CANCER 2012; 31:29-35. [PMID: 22200181 PMCID: PMC3777466 DOI: 10.5732/cjc.011.10258] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 09/20/2011] [Accepted: 09/21/2011] [Indexed: 12/14/2022]
Abstract
Tumor necrosis factor-alpha (TNF-α) is an important cytokine in generating an immune response against infection with hepatitis C virus (HCV). The functions of TNF-α may be altered by single-nucleotide polymorphisms (SNPs) in its gene structure. We hypothesized that SNPs in TNF-α may be important in determining the outcome of an HCV infection. To test this hypothesis, we investigated the role of the polymorphism -308G/A, which is located in the promoter region of the TNF-α gene, in the progression of HCV infection in Egyptian patients using a quantitative real-time polymerase chain reaction (qRT-PCR). The distribution of this polymorphism and its impact on the serum level of TNF-α was compared between 90 HCV-infected patients [45 with HCV-induced cirrhosis and 45 with HCV-related hepatocellular carcinoma (HCC)] and 45 healthy Egyptian volunteers without any history of liver disease. Our results showed that at the TNF-α -308 position, the G/G allele was most common (78.5%) in the study population, with the G/A and A/A alleles occurring less frequently (13.3% and 8.1%, respectively). Frequencies of G/G, G/A, and A/A genotypes were 87%, 7%, and 6% in patients with liver cirrhosis and were 94%, 4%, and 2% in patients with HCC, respectively. Serum levels of TNF-α were significantly higher in HCV-infected patients than in healthy controls, indicating that the TNF-α -308 polymorphism does not influence the production of TNF-α. The serum level of TNF-α was positively correlated with HCV infection. Taken together, these findings suggest that the TNF-α -308 polymorphism may not be a host genetic factor associated with the severity of HCV infection, but may be an independent risk factor for HCC.
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Affiliation(s)
- Roba M Talaat
- Molecular Biology Department, Menofia University, Sadat, Egypt.
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Polymorphisms of tumor necrosis factor-alpha and hepatocellular carcinoma risk: a HuGE systematic review and meta-analysis. Dig Dis Sci 2011; 56:2227-36. [PMID: 21336601 DOI: 10.1007/s10620-011-1617-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2010] [Accepted: 02/01/2011] [Indexed: 02/05/2023]
Abstract
BACKGROUND Studies investigating the associations between tumor necrosis factor-alpha (TNFA) polymorphisms and hepatocellular carcinoma (HCC) risk report conflicting results. We conducted a meta-analysis to assess the association between TNFA gene TNFA-308(G/A), TNFA-238(G/A), TNFA-863(C/A), TNFA-857(C/T), TNFA-1031 (T/C) polymorphisms and HCC susceptibility. METHODS Two investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Database. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for TNFA polymorphisms and HCC were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. RESULTS This meta-analysis included 17 case-control studies, which included 2,357 HCC cases and 3,161 controls. Overall, the variant genotypes AA/AG of -308G/A were associated with a significantly increased HCC risk, when compared with GG genotype (AA vs. GG, OR=1.97, 95%CI=1.01-3.83; AG vs. GG, OR=1.88, 95%CI=1.23-2.88; AA/AG vs. GG, OR=1.80, 95%CI=1.19-2.72). When stratifying for ethnicity, significantly elevated HCC risk was found among Asians. Moreover, similar results were observed between TNFA-238G/A, TNFA-863C/A polymorphisms and HCC risk among Asians (for -238G/A, AG vs. GG OR=1.63, 95%CI=1.17-2.26, AA/AG vs. GG OR=1.61, 95%CI=1.16-2.24; for -863 C/A, AC vs. CC OR=1.72, 95%CI=1.03-2.88, AA/AC vs. CC OR=1.71, 95%CI=1.02-2.86), while no associations were observed between TNFA-857C/T, TNFA-1031T/C polymorphisms and HCC susceptibility. CONCLUSIONS This meta-analysis shows that TNFA-308G/A, TNFA-238G/A and TNFA-863C/A polymorphisms may be associated with HCC among Asians. TNFA-857C/T and TNFA-1031T/C polymorphisms were not detected to be related to the risk for HCC.
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Association of TNF-alpha genetic polymorphisms with hepatocellular carcinoma susceptibility: a case-control study in a Han Chinese population. Int J Biol Markers 2011; 26:181-7. [PMID: 21928250 DOI: 10.5301/jbm.2011.8580] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/04/2011] [Indexed: 12/16/2022]
Abstract
The single nucleotide polymorphisms (SNPs) within the tumor necrosis factor-a (TNF-a) gene promoter region have been reported to be associated with susceptibility to various types of cancers. A case-control study (126 hepatocellular carcinoma [HCC] patients and 126 normal controls) was conducted to elucidate their possible association with the risk of hepatitis B virus (HBV)-related HCC in a Han Chinese population. TNF-alpha polymorphisms -1031T/C, -863C/A, -857C/T, -308G/A, and -238G/A were genotyped by polymerase chain reaction (PCR) and direct DNA sequencing. Disease associations were analyzed by the chi-square test or Fisher's exact test. When analyzed by overall groups, no significant differences in genotype and allele distributions were observed between the control and cases. However, stratified analysis according to sex showed that the frequency of the homozygous C allele of the -857 polymorphism was lower in female cases than in female controls (62.9% vs. 88.9%, p=0.026). In addition, further haplotype analysis revealed that the TCCGA (-1031/-863/-857/-308/-238) was more frequent in controls than cases (p=0.018; odds ratio = 0.266; 95% confidence interval, 0.083-0.857). These results indicated that the TNF-alpha-857C/T polymorphism may modify HBV-related HCC risk among women, and the haplotype TCCGA (-1031/-863/-857/-308/-238) may account for a decreased susceptibility to HCC development in the Han Chinese population. Additional studies in patients with different ethnic backgrounds are needed to validate these finding and to further explore the genetic pathogenesis of HBV-related HCC.
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Li M, You Q, Wang X. Association between polymorphism of the tumor necrosis factor alpha-308 gene promoter and colon cancer in the Chinese population. Genet Test Mol Biomarkers 2011; 15:743-7. [PMID: 21631297 DOI: 10.1089/gtmb.2011.0068] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Tumor necrosis factor (TNF) is a type of cytokine that inhibits tumorigenesis. Several studies have assessed the relationship between the polymorphism of TNF-alpha 308G/A and the susceptibility to colon cancer; however, the results have been controversial. A case-control study was carried out to investigate whether TNF-alpha 308G/A gene polymorphism was associated with the risk of colon cancer in a group of 180 cases and 180 controls from Heilongjiang, China. DNA was isolated from peripheral blood, and gene polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Results of our study showed that colon cancer cases had a significantly higher frequency of TNF-alpha 308AA genotype (odds ratio=9.42, 95% confidence interval=1.18, 75.15; p=0.03) than controls. When stratified by the tumor location, tumor size, growth pattern, differentiation, and stage of colon cancer, no statistically significant results was observed. The present study demonstrated that TNF-alpha 308AA genotype was associated with a higher risk of colon cancer in the Chinese population. Confirmation of these findings in other populations is required.
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Affiliation(s)
- Mingqi Li
- Department of Colorectal Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
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Yang Y, Luo C, Feng R, Bi S. The TNF-α, IL-1B and IL-10 polymorphisms and risk for hepatocellular carcinoma: a meta-analysis. J Cancer Res Clin Oncol 2011; 137:947-52. [PMID: 21107607 DOI: 10.1007/s00432-010-0959-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2010] [Accepted: 11/02/2010] [Indexed: 02/07/2023]
Abstract
OBJECTIVE TNF-α-308 G/A, TNF-α-238 G/A, IL-1B-31 T/C, IL-1B-511 C/T, and IL-10-1082 G/A polymorphisms have been reported to influence the risk for hepatocellular carcinoma (HCC) in many studies; however, the results still remains controversial and ambiguous. The aim of this study was to determine more precise estimations for the relationship between TNF-α, IL-1B, and IL-10 polymorphisms and the risk for HCC by meta-analysis. METHODS Electronic searches for all publications were conducted on associations between these variants and HCC in several databases through September 2010. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated to estimate the strength of this association in a random-effect model. Twenty studies were identified, involving 2,763 HCC patients and 4,152 controls. RESULTS This meta-analysis showed significant association between TNF-α-308 polymorphism and HCC (AA + GA vs. GG: OR = 1.74, 95% CI = 1.12-2.72). In Caucasian and Asian subgroups, OR values (95% CI) were 1.49 (0.58-3.82) and 1.84 (1.06-3.20), respectively. While the ORs for TNF-α-238 G/A, IL-1B-31 T/C, -511 C/T and IL-10-1082 G/A polymorphisms and HCC were 1.37 (0.95-2.00), 1.24 (0.99-1.55), 1.12 (0.66-1.88) and 0.91 (0.74-1.12), respectively. The sensitivity analysis further strengthened the overall strong positive correlations. No publication bias was observed in this study. CONCLUSIONS TNF-α-308 G/A polymorphism is assumed to confer a higher risk for HCC, especially in Asian population. TNF-α-238 G/A, IL-1B-31 T/C, -511 C/T, and IL-10-1082 G/A polymorphisms were not detected to be related to the risk for HCC.
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Affiliation(s)
- Yu Yang
- Department of Oncology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
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Jiao H, Wang W, Wang H, Wu Y, Wang L. Tumor necrosis factor alpha 308 G/A polymorphism and Guillain-Barré syndrome risk. Mol Biol Rep 2011; 39:1537-40. [PMID: 21604171 DOI: 10.1007/s11033-011-0892-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2011] [Accepted: 05/17/2011] [Indexed: 10/18/2022]
Abstract
Guillain-Barré syndrome (GBS) is an inflammatory disorder that may implicate proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) in its pathogenesis. The association between TNF-alpha 308 G/A polymorphism and GBS largely remains unknown. The aim of this study was to investigate the association between TNF-alpha 308 G/A polymorphism and GBS in Chinese Han patients. TNF-alpha 308 G/A polymorphism in 150 GBS patients and 150 healthy controls were studied using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Patients with GBS had a significantly higher frequency of TNF-alpha 308AA genotype [odds ratio (OR) = 3.79, 95% confidence interval (CI) = 1.03, 13.94; P = 0.04] than controls. When stratified by the GBS subtype, there was a significantly higher frequency of TNF-alpha 308AA genotype in patients with AMAN (OR = 6.05, 95% CI = 1.45, 25.31; P = 0.01) and AMSAN (OR = 5.56, 95% CI = 1.18, 26.23; P = 0.03) than controls. There was no significant difference in the distribution of each genotype between patients with AIDP and the control group. These data indicated that TNF-alpha 308AA genotype was associated with a higher risk of GBS in Chinese population, especially to AMAN and AMSAN.
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Affiliation(s)
- Hong Jiao
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, Heilongjiang 150086, People's Republic of China
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Shi Z, Du C. Tumor necrosis factor alpha 308 G/A polymorphism and hepatocellular carcinoma risk in a Chinese population. Genet Test Mol Biomarkers 2011; 15:569-72. [PMID: 21401328 DOI: 10.1089/gtmb.2011.0008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The genetic basis of susceptibility to hepatocellular carcinoma (HCC) is poorly understood. Tumor necrosis factor alpha (TNF-α) is a cytokine that may act as an endogenous tumor promoter. The association between TNF-α 308 G/A polymorphism and HCC risk remains unclear. AIM The aim of this study was to investigate the association between TNF-α 308 G/A polymorphism and HCC risk in a Chinese population. METHODS The study population consisted of 88 patients with documented HCC and 88 healthy controls. The gene polymorphism of TNF-α was analyzed by polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS HCC patients had a significantly lower frequency GG (odds ratio=0.36; 95% confidence interval=0.13, 0.94; p=0.04) and G allele (odds ratio=0.58; 95% confidence interval=0.37, 0.90; p=0.01) than healthy controls. When stratifying for tumor size and cirrhosis, no statistically significant results were found. CONCLUSION This study suggested that TNF-α -308GG and G allele were associated with a modest decrease in the risk of HCC in Chinese population.
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Affiliation(s)
- Zhengrong Shi
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Genetic Risk Markers for Nasopharyngeal Carcinoma in Portugal: Tumor Necrosis Factor Alpha −308G >A Polymorphism. DNA Cell Biol 2011; 30:99-103. [DOI: 10.1089/dna.2010.1086] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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Qin H, Liu B, Shi T, Liu Y, Sun Y, Ma Y. Tumour necrosis factor-alpha polymorphisms and hepatocellular carcinoma: a meta-analysis. J Int Med Res 2010; 38:760-8. [PMID: 20819413 DOI: 10.1177/147323001003800304] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The genetic basis of susceptibility to hepatocellular carcinoma (HCC) is poorly understood. To summarize the quantitative association between polymorphisms of the tumour necrosis factor-alpha (TNFA) gene and HCC, a meta-analysis of relevant studies was performed. Ten case-control studies involving 1421 HCC cases were identified from the Medline, Embase and Current Contents databases. Combined results based on all studies showed that patients with HCC had a significantly lower frequency of the TNFA gene polymorphism -308GG than healthy controls. When stratifying for race, results were similar among Asians and Caucasians. When comparing with hepatitis B virus infection cases, no statistical association was found. This meta-analysis suggests that TNFA -308GG gene polymorphism is associated with a modest decrease in the risk of HCC.
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Affiliation(s)
- H Qin
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
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Singhal S, Kohaar I, Bharadwaj M, Shukla DK, Das BC, Kar P. Association of tumor necrosis factor-alpha gene promoter polymorphisms with acute viral hepatitis in the Indian population. Dig Dis Sci 2010; 55:1106-12. [PMID: 19390969 DOI: 10.1007/s10620-009-0799-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Accepted: 03/17/2009] [Indexed: 01/13/2023]
Abstract
The key elements that determine the host response to either the self-limited or a severe fulminant form of liver disease are unclear. We have investigated the potential association of single nucleotide polymorphisms (SNPs) in the promoter region of tumor necrosis factor-alpha (TNFalpha) in their susceptibility to acute viral hepatitis (AVH) and fulminant hepatic failure (FHF) patients exhibiting specific viral etiology. A total of 124 individuals including 64 cases comprising 27 FHF, 37 AVH, and 60 healthy controls were recruited. SNPs at -238 (G/A), -308 (G/A), -857 (C/T), and -863 (C/A) of TNFalpha were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by direct sequencing. Serum levels of TNFalpha were determined at admission and death or recovery. Association between the TNFalpha genotype and susceptibility to FHF was not evident; however, carrier genotypes in relation to the -308 (GA/AA) and -857 (CT/TT) loci were found to be significantly (P < or = 0.05) associated with susceptibility to AVH in relation to controls. The mean TNFalpha serum levels at admission were significantly higher (P < 0.001) in FHF than AVH patients, but no marked difference was observed between FHF-E (expired; n = 17) and FHF-S (survivors; n = 10), though the former were comparatively higher. This study suggests that SNPs at -308 and -857 of the TNFalpha promoter may represent an increased risk for the development of AVH but not for FHF in the Indian population.
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Affiliation(s)
- Shashideep Singhal
- Division of Gastroenterology, Department of Medicine, Maulana Azad Medical College and Lok Nayak Hospital, BL Taneja Block, BSZ Marg, New Delhi, 110001, India.
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Skibola CF, Bracci PM, Nieters A, Brooks-Wilson A, de Sanjosé S, Hughes AM, Cerhan JR, Skibola DR, Purdue M, Kane E, Lan Q, Foretova L, Schenk M, Spinelli JJ, Slager SL, De Roos AJ, Smith MT, Roman E, Cozen W, Boffetta P, Kricker A, Zheng T, Lightfoot T, Cocco P, Benavente Y, Zhang Y, Hartge P, Linet MS, Becker N, Brennan P, Zhang L, Armstrong B, Smith A, Shiao R, Novak AJ, Maynadie M, Chanock SJ, Staines A, Holford TR, Holly EA, Rothman N, Wang SS. Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) polymorphisms and risk of non-Hodgkin lymphoma in the InterLymph Consortium. Am J Epidemiol 2010; 171:267-76. [PMID: 20047977 PMCID: PMC2842204 DOI: 10.1093/aje/kwp383] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2009] [Accepted: 10/26/2009] [Indexed: 12/13/2022] Open
Abstract
In an International Lymphoma Epidemiology Consortium pooled analysis, polymorphisms in 2 immune-system-related genes, tumor necrosis factor (TNF) and interleukin-10 (IL10), were associated with non-Hodgkin lymphoma (NHL) risk. Here, 8,847 participants were added to previous data (patients diagnosed from 1989 to 2005 in 14 case-control studies; 7,999 cases, 8,452 controls) for testing of polymorphisms in the TNF -308G>A (rs1800629), lymphotoxin-alpha (LTA) 252A>G (rs909253), IL10 -3575T>A (rs1800890, rs1800896), and nucleotide-binding oligomerization domain containing 2 (NOD2) 3020insC (rs2066847) genes. Odds ratios were estimated for non-Hispanic whites and several ethnic subgroups using 2-sided tests. Consistent with previous findings, odds ratios were increased for "new" participant TNF -308A carriers (NHL: per-allele odds ratio (OR(allelic)) = 1.10, P(trend) = 0.001; diffuse large B-cell lymphoma (DLBCL): OR(allelic) = 1.23, P(trend) = 0.004). In the combined population, odds ratios were increased for TNF -308A carriers (NHL: OR(allelic) = 1.13, P(trend) = 0.0001; DLBCL: OR(allelic) = 1.25, P(trend) = 3.7 x 10(-6); marginal zone lymphoma: OR(allelic) = 1.35, P(trend) = 0.004) and LTA 252G carriers (DLBCL: OR(allelic) = 1.12, P(trend) = 0.006; mycosis fungoides: OR(allelic) = 1.44, P(trend) = 0.015). The LTA 252A>G/TNF -308G>A haplotype containing the LTA/TNF variant alleles was strongly associated with DLBCL (P = 2.9 x 10(-8)). Results suggested associations between IL10 -3575T>A and DLBCL (P(trend) = 0.02) and IL10 -1082A>G and mantle cell lymphoma (P(trend) = 0.04). These findings strengthen previous results for DLBCL and the LTA 252A>G/TNF -308A locus and provide robust evidence that these TNF/LTA gene variants, or others in linkage disequilibrium, are involved in NHL etiology.
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Affiliation(s)
- Christine F Skibola
- 237A Hildebrand Hall, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-7360, USA.
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Jung KW, Ha E, Yu GI, Kim SJ, Chung WJ, Jang BK, Lee JJ, Shin DH, Hwang JS. TNFα promoter polymorphism is a risk factor for susceptibility in hepatocellular carcinoma in Korean population. Clin Chim Acta 2009; 407:16-9. [DOI: 10.1016/j.cca.2009.06.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2009] [Revised: 06/12/2009] [Accepted: 06/12/2009] [Indexed: 12/15/2022]
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Akkiz H, Bayram S, Bekar A, Ozdil B, Akgöllü E, Sümbül AT, Demiryürek H, Doran F. G-308A TNF-alpha polymorphism is associated with an increased risk of hepatocellular carcinoma in the Turkish population: case-control study. Cancer Epidemiol 2009; 33:261-4. [PMID: 19683483 DOI: 10.1016/j.canep.2009.06.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2008] [Revised: 06/04/2009] [Accepted: 06/05/2009] [Indexed: 12/16/2022]
Abstract
BACKGROUND Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine that may act as an endogenous tumor promoter. A genetic polymorphism of TNF-alpha gene at position -308 promoter region is involved in the regulation of expression level and has been found to be associated with susceptibility to various types of cancer. METHODS To determine the association of the TNF-alpha gene G-308A polymorphism on the risk of hepatocellular carcinoma (HCC) in a Turkish population, a hospital-based case-control study was designed consisting of 110 diagnosis subjects with hepatocellular carcinoma and 110 cancer-free control subjects matched on age, gender, smoking and alcohol status. The genotype frequency of this polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS The distribution G-308A genotype was significantly associated with the risk of HCC (p<0.001, odds ratio [OR]=4.75, 95% confidence interval [CI]=2.25-9.82 for -308 AA/GA genotypes versus GG genotype). CONCLUSION We suggested that the presence of the high producer allele -308A in the TNF-alpha gene appears to be associated with an increased risk for the development of HCC in Turkish population.
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Affiliation(s)
- Hikmet Akkiz
- Department of Gastroenterology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey
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Abstract
Tumor necrosis factor (TNF) is a multifunctional cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory cytokine, TNF is secreted by inflammatory cells, which may be involved in inflammation-associated carcinogenesis. TNF exerts its biological functions through activating distinct signaling pathways such as nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK). NF-kappaB is a major cell survival signal that is anti-apoptotic, whereas sustained JNK activation contributes to cell death. The crosstalk between the NF-kappaB and JNK is involved in determining cellular outcomes in response to TNF. In regard to cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates the growth, proliferation, invasion and metastasis, and tumor angiogenesis of cancer cells. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing cancer cells to TNF-induced apoptosis through inhibiting survival signals such as NF-kappaB, by combined therapy. In this article we provide an overview of the roles of TNF-induced signaling pathways in cancer biology with specific emphasis on carcinogenesis and cancer therapy.
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Affiliation(s)
- Xia WANG
- Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yong LIN
- Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute 2425 Ridgecrest DR., SE, Albuquerque, NM 87108, USA
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Sakamoto T, Higaki Y, Hara M, Ichiba M, Horita M, Mizuta T, Eguchi Y, Yasutake T, Ozaki I, Yamamoto K, Onohara S, Kawazoe S, Shigematsu H, Koizumi S, Tanaka K. Interaction between interleukin-1beta -31T/C gene polymorphism and drinking and smoking habits on the risk of hepatocellular carcinoma among Japanese. Cancer Lett 2008; 271:98-104. [PMID: 18603357 DOI: 10.1016/j.canlet.2008.05.036] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2008] [Revised: 04/07/2008] [Accepted: 05/26/2008] [Indexed: 12/11/2022]
Abstract
The risk of hepatocellular carcinoma (HCC) increases with the severity of hepatic inflammation. Interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha are proinflammatory cytokines with multiple biological effects and may play essential roles in inflammation-linked tumor development. We conducted a case-control study including 209 incident HCC cases and two control groups (275 hospital controls and 381 patients with chronic liver disease [CLD] without HCC) to investigate whether IL-1B and TNF-A gene polymorphisms influence HCC susceptibility with any interaction with alcohol and tobacco. By comparing HCC cases with CLD patients, we found that IL-1B -31T/C polymorphism was associated with HCC risk among never drinkers and current smokers; adjusted odds ratios (and 95% confidence intervals) for C/T and T/T genotypes compared with C/C genotype were 1.70 (0.76-3.77) and 2.46 (1.05-5.76) (P trend=0.03), respectively, among never drinkers, and 1.53 (0.60-3.99) and 2.54 (0.81-7.95) (P trend=0.11), respectively, among current smokers. Similarly, HCC risk associated with heavy alcohol intake and current smoking differed by this polymorphism among CLD patients. IL-1B -31T/C polymorphism may modify HCC risk in relation to alcohol intake or smoking.
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Affiliation(s)
- Tatsuhiko Sakamoto
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
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Danforth KN, Rodriguez C, Hayes RB, Sakoda LC, Huang WY, Yu K, Calle EE, Jacobs EJ, Chen BE, Andriole GL, Figueroa JD, Yeager M, Platz EA, Michaud DS, Chanock SJ, Thun MJ, Hsing AW. TNF polymorphisms and prostate cancer risk. Prostate 2008; 68:400-7. [PMID: 18196539 DOI: 10.1002/pros.20694] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Inflammation has been hypothesized to increase prostate cancer risk. Tumor necrosis factor (TNF) is an important mediator of the inflammatory process, but the relationship between TNF variants and prostate cancer remains unclear. METHODS We examined associations between six TNF single nucleotide polymorphisms (SNPs) (rs1799964, rs1800630, rs1799724, rs1800629, rs361525, rs1800610) and prostate cancer risk among 2,321 cases and 2,560 controls from two nested case-control studies within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 2,561, 5 SNPs) and the Cancer Prevention Study II Nutrition Cohort (Nutrition Cohort, n = 2,320, 6 SNPs). Odds ratios and 95% confidence intervals were estimated for individual SNPs and haplotypes in each cohort separately and in pooled analyses. RESULTS No TNF SNP was associated with prostate cancer risk in PLCO (P-trend > or = 0.16), while in the Nutrition Cohort, associations were significant for 2 highly correlated variants (rs1799724, 1800610, r2 = 0.95; P-trend = 0.04 and 0.02, respectively). In pooled analyses, no single SNP was associated with prostate cancer risk (P-trend > or = 0.08). After adjustment for multiple testing, no SNP was associated with prostate cancer risk in either cohort individually or in the pooled analysis (P-trend all > or = 0.10). Haplotypes based on 5 TNF SNPs did not vary by case/control status in PLCO, but showed marginal associations in the Nutrition Cohort (global P = 0.06) and the pooled analysis (global P = 0.05). CONCLUSIONS Despite somewhat suggestive haplotype results, overall our study does not support an association between TNF variants and prostate cancer risk.
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Affiliation(s)
- Kim N Danforth
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20852, USA
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Gupta R, Sharma SC, Das SN. Association of TNF-alpha and TNFR1 promoters and 3' UTR region of TNFR2 gene polymorphisms with genetic susceptibility to tobacco-related oral carcinoma in Asian Indians. Oral Oncol 2008; 44:455-63. [PMID: 18206417 DOI: 10.1016/j.oraloncology.2007.06.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2007] [Revised: 06/05/2007] [Accepted: 06/06/2007] [Indexed: 01/20/2023]
Abstract
Tobacco-related oral squamous cell carcinoma is a common malignancy in Asian people. It accounts for almost 40% of cancers among Indian men and 3% in the Western world. Smokeless tobacco has been shown to induce tumor necrosis factor-alpha (TNF-alpha), which, along with its receptors, is over-expressed in people with oral carcinoma. Single nucleotide polymorphisms (SNPs) in TNF-alpha and TNF receptor genes may affect their expression and may be a potential determinant of susceptibility to tobacco-related oral carcinomas. We assessed SNPs in TNF-alpha(-308, -238) and TNF receptor 1 (TNFR1; -609) promoters by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and at four sites of TNF receptor 2 gene (TNFR2; exon 9 site 1176; exon 10 sites 1663, 1668 and 1690) by PCR-sequence-specific primers (PCR-SSP) techniques, respectively, in 94 patients and 130 healthy controls. TNF-alpha-308 G allele was significantly lower (Pc=0.004; OR=3.85), whereas A allele was significantly higher (Pc=0.004; OR=0.25) in patients compared with controls. No significant change was observed at -238 promoter site between the two groups. In the case of TNF receptors, both TNFR1 -609 TT (Pc=0.006; OR=15.3) and TNFR2 1690 CT (Pc=0.018; OR=5.6) genotypes were significantly lower in patients compared with controls. It seems that TNF-alpha-308 G/A may be related to susceptibility, whereas -609 TT TNFR1 and 1690 C/T TNFR2 SNPs may be protective to tobacco-related oral squamous cell carcinoma. These SNPs may be useful as a marker for high-risk groups among Asian Indians.
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Affiliation(s)
- Reeshu Gupta
- Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India
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Kloth JN, Gorter A, ter Haar N, Corver WE, Jordanova ES, Kenter GG, Fleuren GJ. Lack of TNFα mRNA expression in cervical cancer is not associated with loss of heterozygosity at 6p21.3, inactivating mutations or promoter methylation. Mol Immunol 2008; 45:152-9. [PMID: 17560652 DOI: 10.1016/j.molimm.2007.04.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2007] [Revised: 04/21/2007] [Accepted: 04/23/2007] [Indexed: 10/23/2022]
Abstract
Infection with oncogenic human papillomavirus (HPV) is considered to be the major etiologic event for cervical cancer. Tumor necrosis factor alpha (TNFalpha), a proinflammatory cytokine, may be involved in orchestrating an antitumor immune response against human papillomavirus expressing cervical cancer cells. Hence, loss of TNFalpha could be advantageous for tumor cells to escape immune clearance. The aim of our study was to investigate TNFalpha gene expression and epigenetic characteristics associated with the loss of TNFalpha expression in cervical cancer. To this end, we examined TNFalpha expression, loss of heterozygosity (LOH) at 6p21.3, the locus of TNFalpha, mutational status of the TNFalpha locus, loss of the TNFalpha promoter variant 2 allele and CpG hypermethylation of the TNFalpha promoter. RNA in situ hybridization showed absence of TNFalpha expression in 45% of 63 tumors. LOH occurred in 57% of the tumors and was not concordant with absence of TNFalpha mRNA. No mutations in the TNFalpha gene were identified in 15 cases deficient in TNFalpha expression exhibiting LOH. Furthermore, lack of TNFalpha expression did not correlate with promoter methylation. In conclusion, TNFalpha mRNA expression is absent in nearly half of the cervical tumors analyzed. Neither promoter methylation nor genetic causes for lack of expression were evident.
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Affiliation(s)
- Judith N Kloth
- Department of Pathology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
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Kummee P, Tangkijvanich P, Poovorawan Y, Hirankarn N. Association of HLA-DRB1*13 and TNF-alpha gene polymorphisms with clearance of chronic hepatitis B infection and risk of hepatocellular carcinoma in Thai population. J Viral Hepat 2007; 14:841-848. [PMID: 18070287 DOI: 10.1111/j.1365-2893.2007.00880.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Considerable evidence suggests that host genetic factor play an important role in the pathogenesis and clinical outcome of chronic hepatitis B virus (HBV) infection in several ethic groups. Association study was performed included 150 chronic HBV patients, 100 resolved hepatitis B and 150 healthy individuals with similar ethic background. Interestingly, human leucocyte antigen (HLA)-DR13 show a strong association with the clearance of HBV [odds ratio (OR) = 0.04, 95% confidence interval (CI) = 0.00-0.26, corrected P-value (P(c)) = 0.0008] similar to reports from several ethic groups. TNF-alpha promoter polymorphisms (-863, -308 and -238) were also analysed. Only -863 C allele was found to be significantly decreased in chronic HBV patients compared with healthy control (P(c) = 0.03, OR = 0.54, 95% CI = 0.35-0.84 respectively). This -863C allele was not in linkage disequilibrium with HLA-DR13 suggesting that other genetic markers linked with -863C might influence clearance of chronic HBV infection in Thai. When stratified chronic HBV patients into patients without hepatocellular carcinoma (HCC) and with HCC, the -863 A allele was significantly increased in the HCC group compared to healthy control (P(c) = 0.003, OR = 2.61, 95% CI = 1.49-4.60). Haplotype analysis (-863/-308/-238) revealed that the homozygosity of the haplotype (CGG/CGG) was a protective marker for HCC (OR = 0.37, 95% CI = 0.17-0.79, P(c) = 0.02). One can propose that carriers of -863A genotype are associated with increased levels of TNF-alpha in the liver in response to HBV infection and induce hapatocyte damage that may finally lead to HCC development. Additional study is needed to validate these finding and to further explore the genetic pathogenesis of HBV infection.
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Affiliation(s)
- P Kummee
- Inter-Department of Medical Microbiology, Graduate School, Chulalongkorn University, Bangkok, Thailand
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Jeng JE, Tsai JF, Chuang LY, Ho MS, Lin ZY, Hsieh MY, Chen SC, Chuang WL, Wang LY, Yu ML, Dai CY, Chang JG. Tumor necrosis factor-alpha 308.2 polymorphism is associated with advanced hepatic fibrosis and higher risk for hepatocellular carcinoma. Neoplasia 2007; 9:987-992. [PMID: 18030367 PMCID: PMC2077890 DOI: 10.1593/neo.07781] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2007] [Revised: 09/12/2007] [Accepted: 09/12/2007] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS Host genetic factor and hepatic fibrosis may predispose to risk for hepatocellular carcinoma (HCC). This study aimed to assess the association between tumor necrosis factor (TNF) alpha polymorphism and hepatic fibrosis, and risk for HCC. METHODS One hundred eight pairs of gender-matched and age-matched patients with HCC and unrelated healthy controls were genotyped for TNF308.2 and TNF238.2 alleles with polymerase chain reaction and direct sequencing. RESULTS The frequency of TNF308.1/TNF308.2 genotype in cases was higher than that in controls [odds ratio (OR) = 4.37]. Multivariate analysis indicated that TNF308.2 allele (OR = 3.23), hepatitis B surface antigen (OR = 17.17), and antibodies to hepatitis C virus (OR = 45.52) were independent risk factors for HCC. Surrogate markers for significant fibrosis implied that cases with the TNF308.2 allele have more advanced liver fibrosis. Moreover, multivariate analysis indicated that cirrhosis with Child-Pugh grade C, low serum albumin, and low platelet count were independent risk factors for carrying the TNF308.2 allele. CONCLUSIONS TNF308.2 allele carriage and chronic hepatitis B virus/hepatitis C virus infection are independent risk factors for HCC. Carriage of the TNF308.2 allele correlates with disease severity and hepatic fibrosis, which may contribute to a higher risk for HCC.
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Affiliation(s)
- Jen-Eing Jeng
- Department of Clinical Laboratory, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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