摘要
目的
肝癌是我国最常见的恶性肿瘤之一,其发病机制尚不十分清楚。现代遗传学观点认为,肝癌等复杂疾病属于多基因疾病,是由环境因素和机体自身的遗传因素协同作用,经过多个阶段而发生和发展的。鉴定肝癌的遗传易感基因将有助于揭示肝癌的发病机制,并为实现肝癌的风险预测及个体化医疗奠定理论基础。
一方面,动物模型和人群流行病学资料皆显示,雌激素可作为肿瘤促进剂促进肝癌的发生。雌激素通过雌激素代谢酶完成体内转化,并通过其受体发挥其生物学作用,因而提示雌激素受体和雌激素代谢酶基因的多态性可能影响个体对肝癌的遗传易感性。另一方面,氧化应激在肝癌的发生中起着重要作用,而体内的抗氧化体系可通过多种途径来抑制和清除活性氧的产生,以减轻氧化损伤的程度。因此,体内抗氧化酶基因的多态性也可能影响个体对肝癌的易感性。为证实上述两假说,我们在第一部分及第二部分研究中采用基于候选基因的关联研究策略及病例-对照实验设计,选取参与雌激素生理作用的雌激素代谢酶、雌激素受体基因及参与自由基清除的抗氧化酶基因作为候选基因,系统的研究了这些基因的多态性与肝癌易感性的相关性。
此外,在过去4年中,本课题组系统发掘了120余个人类重要功能基因的1400余个单核苷酸多态性(Single nucleotide polymorphism, SNP)位点(包括调控区、编码区和剪接区的SNPs),其中包括肿瘤转移抑制基因KAI1/CD82启动子区(-1572至+415)的SNPs。大量实验证实KAI1基因对大多数肿瘤的转移起抑制作用,与肿瘤的侵袭及预后密切相关。因此,揭示KAI1/CD82基因在肿瘤组织中的表达调控机制及生物学作用,可为肿瘤的治疗和判断预后提供新思路。为此,我们选取CD82启动子区的两个常见SNP位点(rs934178和T-262G)进行了系统的功能研究,以期揭示启动子区SNP位点对CD82表达调控的影响及机制。
材料与方法
1.关联研究中,研究对象包括434例肝癌患者和480例非癌症对照,病例采集于广西壮族自治区肿瘤医院,居住地局限于广西壮族自治区扶绥县及其周边地区,对照来自于同一地区的社区人群,对病例与对照组人群的性别、年龄、居住地等因素进行频数匹配。
2.关联研究中,采用聚合酶链式反应-限制性酶切片段多态性(Polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)方法对雌激素受体β(Estrogen receptorβ, ESR2)的4个SNP位点(G1082A、A1730G、rs1256054和T1057G)、雌激素代谢酶的8个SNP位点(CYP17 Msp AI、CYP19 Trp39Arg、CYP19 I/D、CYP1A1 MspI、CYP1A1 Ile462Val、CYP1B1 Val432Leu、COMT Ala72Ser和COMT Val158Met)和抗氧化酶的6个SNP位点(CuZnSOD A1934C、MnSOD Ala16Val、ECSOD Ala40Thr、ECSOD Arg213Gly、CAT C-262T和GPx-1 Pro198Leu)进行基因分型。采用片断分析技术对及CYP19的短串联重复标记(TTTA)n进行基因分型。
3.在SNP的功能研究中,采用电泳迁移率实验(Electrophoretic mobility shift assay, EMSA)检测了CD82启动子区T-262G多态性位点对转录因子与DNA结合的影响。采用双荧光素酶报告基因瞬时转染HepG2及293细胞,检测调控区的两个SNP位点(rs934178和T-262G)对-1572至+493区段启动子活性的影响。
4.在遗传关联分析中,采用PHASE软件构建单倍型;采用Arlequin软件包计算LD模式的两个参数(Lewontin’s D’及r2)。采用SPSS14.0统计软件的非条件Logistc回归模型计算各基因型与肝癌风险的相关性,分析时首先对HBV携带状态进行分层,然后对性别、年龄、吸烟、饮酒等混杂因素进行分层,结果经性别、年龄、吸烟、饮酒及吸烟量(年包数,pack-year)等因素校正,对所有统计结果进行Bonferroni多重检验校正。在功能研究中,采用SPSS14.0统计软件的单因素方差分析比较不同转染组荧光素酶相对活性的差异。
结果
1.在ESR2和雌激素代谢酶基因多态性与肝癌的遗传易感性研究中,基因分型结果显示,中国南方人群中不存在ESR2 T1057G多态性位点及CYP19 (TTTA)n多态性位点。其余位点的关联分析显示,经Bonferroni多重检验校正后,仅COMT Ala72Ser在总体中与肝癌易感性显著相关,但对HBV携带状态进行分层后,该多态性位点与HBV携带者或非HBV携带者的肝癌易感性均无显著关联;其余位点及ESR2、CYP1A1、材料与方法COMT的单倍型/双体型与肝癌的易感性也无显著关联。
2.在抗氧化酶基因多态性与肝癌的遗传易感性研究中,基因分型结果显示,中国南方人群中不存在CuZnSOD A1934C多态性位点,ECSOD Arg213Gly多态性位点次要等位的频率<1%。关联分析结果显示,在总体样本中MnSOD Ala16Val、CAT C-262T和GPx-1 Pro198Leu多态性位点与肝癌的患病风险无显著关联;对受试者的HBV携带状态、性别、年龄、吸烟及饮酒状态进行分层后,上述位点与肝癌的患病风险仍无显著性关联。ECSOD Ala40Thr与总体及HBV携带者的肝癌患病风险无显著关联;而在非HBV携带者中,与Ala/Ala基因型相比,Ala/Thr基因型及Ala/Thr+Thr/Thr基因型均显著增加了肝癌的患病风险(OR = 2.13, 95% CI = 1.25-3.64, P = 0.0057;OR = 1.90, 95% CI = 1.15-3.15, P = 0.012)。对性别、年龄、民族、家族史、吸烟及饮酒状态进行分层后,上述显著性关联分别存在于非HBV携带者的男性组、>49岁组、非汉族组、吸烟组和饮酒组。基因-基因间交互作用分析显示:在总体及非HBV携带者中,与携带两个ECSOD 40Ala等位及一个MnSOD 16Ala等位的个体相比,携带至少一个ECSOD 40Thr等位及两个MnSOD 16Val等位的个体患肝癌的风险显著增加(OR = 2.32, 95% CI = 1.36-3.98, P = 0.0018;OR = 9.02, 95% CI =2.04-39.92, P = 0.0037)。基因-环境交互作用分析显示,MnSOD Ala16Val、ECSOD Ala40Thr、CAT C-262T和GPx-1 Pro198Leu与吸烟、饮酒、性别、年龄间不存在显著交互作用。
3.在SNP的功能研究中,EMSA结果显示:含有G、T等位的寡核苷酸双链探针均可结合相同分子量的转录因子,但在结合能力上存在明显差异,G等位的结合能力高于T等位。HepG2及293细胞中的报告基因结果显示:CD82基因-1572至+493区域具有较强的启动子活性,四种单倍型的启动子活性具有明显差异,其中C-T单倍型的启动子活性显著高于T-G单倍型(P < 0.01)。
结论
1.ESR2的G1082A、A1730G和rs1256054多态性位点不影响中国南方人群中个体对肝癌的遗传易感性;由上述3个SNP位点组成的ESR2单倍型及双体型也不影响个体对肝癌的易感性。
2.CYP17 Msp AI、CYP19 I/D、CYP19 Trp39Arg、CYP1A1 Msp I、CYP1A1 Ile462Val、CYP1B1 Val432Leu、COMT Ala72Ser和COMT Val158Met等雌激素代谢酶的多态性位点不影响个体对肝癌的遗传易感性;由CYP1A1 Msp I、CYP1A1 Ile462Val组成的CYP1A1单倍型/双体型及由COMT Ala72Ser、COMT Val158Met组成的COMT单倍型/双体型也不影响个体对肝癌的易感性。
3.MnSOD Ala16Val、CAT C-262T和GPx-1 Pro198Leu多态性位点不影响个体对肝癌的遗传易感性;ECSOD Ala40Thr多态性位点与非HBV携带者的肝癌易感性相关,携带至少一个40Thr等位个体患肝癌的风险显著增加;同时,ECSOD Ala40Thr与MnSOD Ala16Val多态性位点间存在显著的交互作用,协同增加肝癌的发生风险。
4.CD82基因启动子区T-262G位点的G、T等位型均可结合相同的转录因子,但结合能力存在差异,rs934178和T-262G两个SNP组成的单倍型可影响CD82的启动子活性。
Background & Aims
Hepatocellular carcinoma (HCC) is one of the most common malignancy in our country. The pathogenesis of HCC is still poorly understood. In fact, hepatocarcinogenesis is a long-term multistage process with the involvement of hereditary and environmental factors. The identification of susceptibility genes contributing to HCC would help to clarify pathophysiologic mechanisms relevant to hepatocarcinogenesis and would assist in predicting individual and population risk of HCC development.
On the one hand, both animal models and human epidemiologic studies have documented that estrogen act as tumor promoters and might induce hepatocarcinogenesis. Estrogens realize their biogenesis, bioavailability and degradation via estrogen-metabolizing enzymes and exert their biological effects through the estrogen receptor (ER) of target cells. So we hypothesize that the estrogen-metabolizing enzymes and estrogen receptor ? may be the excellent candidate susceptibility genes for HCC and the genetic polymorphisms within these genes would result in differences in susceptibility to HCC. On the other hand, an increased oxidant burden may result in nuclear or mitochondrial DNA damage, DNA methylation, lipid peroxidation and regulation of signal transduction pathways and gene expression, which has been implicated in hepatocarcinogenesis. Several antioxidant enzymes assure protection against oxidative damage. So the genetic variation within antioxidant enzymes could also result in genotype-dependent differences in risk of HCC. To test these hypotheses, we investigated the association of the polymorphisms in estrogen-metabolizing enzymes genes, estrogen receptor ? and antioxidant enzymes genes with susceptibility to HCC in chapter I and chapter II.
In the past 4 years, our group has screened SNPs systematically in 128 functionally important genes and discovered 1,400 SNPs in regulatory region, coding region and splicing region, including two common SNPs in the tumor metastasis suppressor gene, KAI1/CD82, regulatory region (-1,572bp to +415bp). Clarifying the influence of these two SNPs on gene expression may highlight a novel therapeutic target for cancer. So we analyzed the function of these two SNPs in the chapterⅢ.
Methods
The case-control study included 434 patients with HCC and 480 control subjects. All subjects were unrelated ethnic adult Chinese and residents in Fusui County and its surrounding regions at Guangxi province, a well-known high-risk region for HCC located in southern China. At recruitment, informed consent was obtained from each subject, and personal information on demographic factors, medical history, tobacco and alcohol use, and family history of HCC were collected via structured questionnaire.
Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay for four SNPs in ESR2 gene (G1082A, A1730G, rs1256054 and T1057G ), eight in estrogen-metabolizing enzymes genes (CYP17 Msp AI, CYP19 Trp39Arg, CYP19 I/D, CYP1A1 MspI, CYP1A1 Ile462Val, CYP1B1 Val432Leu, COMT Ala72Ser and COMT Val158Met), and six in antioxidant enzymes genes (CuZnSOD A1934C, MnSOD Ala16Val, ECSOD Ala40Thr, ECSOD Arg213Gly, CAT C-262T and GPx-1 Pro198Leu). We also genotyped the (TTTA)n variable number of tandem repeats polymorphism in CYP19 gene through GeneScan technique.
Electrophoretic mobility shift assay (EMSA) was conducted to identify potential transcription factors that bind to -262T or -262G probe. To determine whether the polymorphism in the human CD82 promoter will affect the transcription of this gene, PCR amplified promoter fragments of 2065bp with T/C at rs934178 site and T/G at T-262G site were obtained from four heterozygous individuals and subcloned into pGL3 basic vector. Transient transfection was performed in HepG2 and 293 cells using LipofectamineTM 2000 and luciferase activity was determined using a Dual-Luciferase Reporter Assay System.
Associations between polymorphisms and risk of HCC were estimated by unconditional logistic regression analyses using SPSS software (version 14.0; SPSS Inc., Chicago, IL). The odds ratios (ORs) were calculated by logistic regression and adjusted for age, sex, status of smoking and drinking and pack-years of smoking where appropriate. Potential modification effects of the polymorphisms on HCC risk by the above risk factors were assessed by the addition of interaction terms in the logistic model and by separate analyses of subgroups of subjects determined by these factors. In view of the multiple testing, the correction factor n(m-1) (n loci with m alleles each) was applied to correct the significance level. Haplotype frequencies between cases and controls were compared by using theχ2 test. The comparisons between more than two groups were carried out using the analysis of variance (ANOVA) in chapter III.
Results
1. The ESR2 T1057G polymorphism and CYP19 (TTTA)n polymorphism did not exist in this Chinese population. For the other polymorphisms of ESR2 gene and estrogen-metabolizing enzymes genes, except for COMT Ala72Ser polymorphisms, there was no association between these polymorphisms and HCC susceptibility in overall sample. When the subjects were stratified by HBV carriers status, age, gender, family history, smoking status and drinking status, there were no associations observed between the above all polymorphisms and HCC risk. The haplotype and diplotype distribution of ESR2, CYP1A1 and COMT exhibited no significant difference between the cases and controls.
2. The CuZnSOD A1934C polymorphism did not exist in this population and the minor allele frequency of ECSOD Arg213Gly polymorphism was too low. On the basis of logistic regression analysis with adjustment for age, sex, status of smoking and drinking, and pack-years of smoking, there were no significant associations between three polymorphisms (MnSOD Ala16Val, CAT C-262T, GPx-1 Pro198Leu) and HCC susceptibility in overall sample, HBV carriers and non-HBV carriers. When the subjects were stratified by age, gender, family history, smoking status and drinking status, there were also no associations observed. For the ECSOD Ala40Thr polymorphism, no significant association was found between this polymorphism and HCC risk in overall subjects and HBV carriers. However, in non-HBV carriers, individuals with one 40Thr allele (Ala/Thr genotype) (OR = 2.13, 95% CI = 1.25-3.64, P = 0.0057) or at least one 40Thr allele (Ala/Thr and Thr/Thr genotype) (OR = 1.90, 95% CI = 1.15-3.15, P = 0.012) showed significantly higher risk to HCC, compared with Ala/Ala genotype. Although there was no significant interaction between ECSOD Ala40Thr and MnSOD Ala16Val in overall sample, HBV carriers or non-HBV carriers, the combined effects of ECSOD and MnSOD were greater than those for either polymorphism alone in overall sample and non-HBV carriers. Individuals with at least one ECSOD 40Thr allele and two MnSOD 16Val alleles showed increased risk compared with individuals with two ECSOD 40Ala alleles and at least one MnSOD 16Ala allele in overall sample(OR = 2.32, 95% CI = 0.13-0.80, P = 0.0018) and in non-HBV carriers (OR = 9.02, 95% CI =2.04-39.92, P = 0.0037). No interactions between genotypes of four polymorphisms and risk factors were obtained. No gene-gene interactions in these four polymorphisms were obtained.
3. EMSA result showed that both -262T and -262G probe could form protein-DNA complex with HepG2 cell extracts. The G variant gives a more intense complex compared to the T probe, which was entirely competed by 200-fold molar excess of unlabeled G and T probes, respectively. The results indicated that the same protein bound with different affinity to G and T variants, respectively. Expression studies with reporter constructs showed significantly higher transcriptional activity of the C-T haplotype compared with T-G haplotype in HepG2 and 293 cells (P < 0.01).
Conclusions
1. The G1082A, A1730G and rs1256054 polymorphisms in ESR2 did not contribute to the differences in susceptibility to HCC in this Chinese population and the haplotypes and diplotypes based on these three polymorphisms also did not influence susceptibility to HCC.7
2. The eight polymorphisms in estrogen-metabolizing enzymes genes may not play a major role in mediating susceptibility to HCC. The haplotypes and diplotypes of CYP1A1 and COMT also did do not significantly confer an increased risk of HCC.
3. The MnSOD Ala16Val, CAT C-262T and GPx-1 Pro198Leu polymorphisms did not contribute to the differences in susceptibility to HCC. ECSOD genotypes may modify the risk of HCC in non-HBV carriers. ECSOD and MnSOD had combined effects in mediating susceptibility to HCC.
4. G and T variants at T-262G site in CD82 bound the same protein with different affinity. The G variant had higher affinity than the T variant. The haplotypes based on rs934178 and T-262G polymorphisms modified the transcriptional activity of CD82 promoter.
引文
1. Deuffic S, Poynard T, Buffat L, Valleron AJ. Trends in primary liver cancer. Lancet. 1998; 351:214-215.
2. McGlynn KA, Tsao L, Hsing AW, Devesa SS, Fraumeni JF Jr. International trends and patterns of primary liver cancer. Int J Cancer. 2001; 94:290-296.
3. Xue KX. Molecular genetic and epigenetic mechanisms of hepatocarcinogenesis. Ai Zheng. 2005 Jun;24(6):757-68.
4. Chen CJ, Yu MW, Liaw YF. Epidemiological characteristics and risk factors of hepatocellular carcinoma. J Gastroenterol Hepatol. 1997; 12:S294-308.
5. Maeda T, Shimada M, Harimoto N, et al.Role of tissue trace elements in liver cancers and non-cancerous liver parenchyma. Hepatogastroenterology. 2005; 52(61):187-90.
6. Kondoh N, Wakatsuki T, Ryo A, et al. Identification and characterization of genes associated with human hepatocellular carcinogenesis. Cancer Res. 1999; 59(19):4990-6.
7. Frodsham AJ, Zhang L, Dumpis U, et al. Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence. Proc Natl Acad Sci U S A. 2006; 103(24):9148-53.
8. Shastry BS. SNP alleles in human disease and evolution. J Hum Genet. 2002;47(11):561-6.
9. Landegren U, Nilsson M, Kwok PY. Reading bits of genetic information: methods for single-nucleotide polymorphism analysis. Genome Res. 1998; 8(8):769-76.
10. Reich DE, Cargill M, Bolk S, et al. Linkage disequilibrium in the human genome. Nature, 2001, 411(6834): 199 204.
11. Tantoso E, Yang Y, Li KB.How well do HapMap SNPs capture the untyped SNPs? BMC Genomics. 2006; 7:238.
12. Zhang K, Calabrese P, Nordborg M, Sun F. Haplotype block structure and its applications to association studies: power and study designs. Am J Hum Genet. 2002; 71(6):1386-94.
13. Carlson CS, Eberle MA, Kruglyak L, Nickerson DA. Mapping complex disease loci in whole-genome association studies.Nature. 2004; 429(6990):446-52.
14. Dawn Teare M, Barrett JH. Genetic linkage studies. Lancet. 2005; 366(9490):1036-44.
15. Cordell HJ, Clayton DG.Genetic association studies.Lancet. 2005; 366(9491):1121-31.
16. Schaid DJ, Rowland C.Use of parents, sibs, and unrelated controls for detection of associations between genetic markers and diseases. Am J Hum Genet, 1998, 63:1492-1506.
17. Sheffield LJ. Strategies to find new genes involved in drug metabolism. Curr Opin Mol Ther. 2001; 3(6):579-84.
18. Chen X, Wang H, Xie W, et al. Association of CYP1A2 genetic polymorphisms with hepatocellular carcinoma susceptibility: a case-control study in a high-risk region of China. Pharmacogenet Genomics. 2006; 16(3):219-27.
19. Interleukin 1beta gene polymorphism and hepatitis C virus-related hepatocellular carcinoma. Hepatology. 2003; 38(1):267-8; author reply 268-9.
20. Zhai Y, Zhou G, Deng G, et al. Estrogen receptor alpha polymorphisms associated with susceptibility to hepatocellular carcinoma in hepatitis B virus carriers. Gastroenterology. 2006; 130(7):2001-9.
21. Hattersley AT, McCarthy MI. What makes a good genetic association study? Lancet. 2005; 366(9493):1315-23.
22. Savage SA, Chanock SJ. Genetic association studies in cancer: good, bad or no longer ugly? Hum Genomics. 2006 Jun;2(6):415-21
1. Baum JK, Bookstein JJ, Holtz F, Klein EW. Possible association between benign hepatomas and oral contraceptives.Lancet. 1973;2(7835):926-9.
2. Guechot J, Peigney N, Ballet F, et al.Sex hormone imbalance in male alcoholic cirrhotic patients with and without hepatocellular carcinoma. Cancer. 1988;62(4):760-2.
3. Farinati F, De Maria N, Marafin C, et al. Hepatocellular carcinoma in alcoholic cirrhosis: is sex hormone imbalance a pathogenetic factor? Eur J Gastroenterol Hepatol. 1995;7(2):145-50.
4. Yu MC, Yuan JM, Govindarajan S, Ross RK. Epidemiology of hepatocellular carcinoma. Can J Gastroenterol. 2000;14(8):703-9.
5. De Benedetti VM, Welsh JA, Yu MC, Bennett WP. p53 mutations in hepatocellular carcinoma related to oral contraceptive use. Carcinogenesis.1996;17(1):145-9.
6. Yager JD Jr, Yager R. Oral contraceptive steroids as promoters of hepatocarcinogenesis in female Sprague-Dawley rats. Cancer Res. 1980;40:3680-3685.
7. Coe JE, Ishak KG, Ross MJ. Estrogen induction of hepatocellular carcinomas in Armenian hamsters. Hepatology.1990;11:570-577.
8. Eisenfeld AJ, Aten RF. Estrogen receptors and androgen receptors in the mammalian liver. J Steroid Biochem.1987; 27:1109-18.
9. Friedman MA, Demanes DJ, Hoffman PG.Hepatomas: hormone receptors and therapy. Am J Med.1982;73: 362-66.
10. Fisher B, Gunduz N, Saffer EA, Zheng S. Relation of estrogen and its receptor to rat liver growth and regeneration. Cancer Res.1984; 44: 2410-15.
11. Francavilla A, Di Leo A, Eagon PK, et al.Regenerating rat liver: correlations between estrogen receptor localization and deoxyribonucleic acid synthesis. Gastroenterology. 1984;86:552-57.
12. Francavilla A, Polimeno L, Di Leo A, et al.The effect of estrogen and tamoxifen on hepatocyte proliferation in vivo and in vitro. Hepatology. 1989;9: 614-20.
13. Farinati F, De Maria N, Marafin C, et al.1995. Hepatocellular carcinoma in alcoholic cirrhosis: is sex hormone imbalance a pathogenetic factor. Eur J Gastroenterol Hepatol. 1995;7:145-50.
14. Nagasue N, Yu L, Yukaya H, et al. Androgen and oestrogen receptors in hepatocellular carcinoma and surrounding liver parenchyma: impact on intrahepatic recurrence after hepatic resection. Br J Surg. 1995; 82: 542-47.
15. Altucci L, Addeo R, Cicatiello L, et al. 17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells. Oncogene. 1996;12(11):2315-24.
16. Fabio Farinati, R. Cardin , M. Bortolami ,et al. Estrogens receptors and oxidative damage in the liver. Molecular and Cellular Endocrinology. 2002; 193: 85-88.
17. Gold B, Kalush F, Bergeron J, et al. Estrogen receptor genotypes and haplotypes associated with breast cancer risk. Cancer Res 2004;64:8891-8900.
18. Weiderpass E, Persson I, Melhus H, Wedren S, Kindmark A, Baron JA. Estrogen receptor alpha gene polymorphisms and endometrial cancer risk. Carcinogenesis. 2000;21:623-27.
19. Tanaka Y, Sasaki M, Kaneuchi M, Fujimoto S, Dahiya R. Single nucleotide polymorphisms of estrogen receptor alpha in human renal cell carcinoma. Biochem Biophys Res Commun. 2002;296:1200-06.
20. Tanaka Y, Sasaki M, Kaneuchi M, Shiina H, Igawa M, Dahiya R. Polymorphisms of estrogen receptor alpha in prostate cancer. Mol Carcinog. 2003;37:202-08.
21. Zhai Y, Zhou G, Deng G, et al.Estrogen receptor alpha polymorphisms associated with susceptibility to hepatocellular carcinoma in hepatitis B virus carriers.Gastroenterology. 2006;130(7):2001-9. Epub 2006 Mar 6.
22. Zheng SL, Zheng W, Chang BL, et al. Joint effect of estrogen receptor beta sequence variants and endogenous estrogen exposure on breast cancer risk in Chinese women. Cancer Res. 2003;63(22):7624-29.
23. Wang Z, Yoshida S, Negoro K, Kennedy S, Barlow D, Maruo T. Polymorphisms in the estrogen receptor beta gene but not estrogen receptor alpha gene affect the risk of developing endometriosis in a Japanese population. Fertil Steril. 2004;81(6):1650-6.
24. Sundarrajan C, Liao WX, Roy AC, Ng SC. Association between Estrogen Receptor-b Gene Polymorphisms and Ovulatory Dysfunctions in Patients with Menstrual Disorders.J Clin Endocrinol Metab. 2001;86(1):135-39.
25. Simpson E, Lauber M, Demeter M, et al. Regulation of expression of the genes encodingsteroidogenic enzymes. J Steroid Biochem Mol Biol. 1991;40(1-3):45-52.
26. Carey AH, Waterworth D, Patel K, et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet 1994;3:1873-6.
27. Haiman C A, Hankinson S E, Spiegelman D, et al. The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer. Cancer Res.1999; 59: 1015-20.
28. Huang CS, Chern HD, Chang KJ, Cheng CW, Hsu SM, Shen CY. Breast cancer risk associated with genotype polymorphism of the estrogen-metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on cancer susceptibility. Cancer Res. 1999;59(19):4870-5.
29. Haiman CA, Hankinson SE, Colditz GA, Hunter DJ, De Vivo I. A polymorphism in CYP17 and endometrial cancer risk. Cancer Res. 2001;61(10):3955-60.
30. Garner EI, Stokes EE, Berkowitz RS, et al. Polymorphisms of the estrogen-metabolizing genes CYP17 and catechol-O-methyltransferase and risk of epithelial ovarian cancer.Cancer Res. 2002;62(11):3058-62.
31. Crofts F, Taioli E, Trachman J, et al.Functional significance of different human CYP1A1 genotypes. Carcinogenesis. 1994;15(12):2961-3.
32. Landi MT, Bertazzi PA, Shields PG, et al.Association between CYP1A1 genotype, mRNA expression and enzymatic activity in humans. Pharmacogenetics. 1994;4(5):242-6.
33. Song N, Tan W, Xing D, Lin D. CYP 1A1 polymorphism and risk of lung cancer in relation to tobacco smoking: a case-control study in China. Carcinogenesis. 2001;22(1):11-6.
34. Firozi PF, Bondy ML, Sahin AA, et al. Aromatic DNA adducts and polymorphisms of CYP1A1, NAT2, and GSTM1 in breast cancer. Carcinogenesis. 2002;23(2):301-6.
35. Vijayalakshmi K, Vettriselvi V, Krishnan M, Shroff S, Jayanth VR, Paul SF. Cytochrome p4501A1 gene variants as susceptibility marker for prostate cancer.Cancer Biomark. 2005;1(4-5):251-8.
36. Dawling S, Roodi N, Mernaugh RL, Wang X, Parl FF. Catechol-O-methyltransferase (comt)-mediated metabolism of catechol estrogens: comparison of wild-type and variantcomt isoforms. Cancer Res. 2001;61: 6716-22.
37. Sazci A, Ergul E, Utkan NZ, Canturk NZ, Kaya G. Catechol-O-methyltransferase Val 108/158 Met polymorphism in premenopausal breast cancer patients. Toxicology. 2004;204(2-3):197-202.
38. Kushner PJ, Agard DA, Greene GL, et al. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol 2000;74:311–7.
39. Gennari L, Merlotti D, De Paola V, et al.Estrogen receptor gene polymorphisms and the genetics of osteoporosis: a HuGE review.Am J Epidemiol. 2005;161(4):307-20.
40. Iavarone M, Lampertico P, Seletti C, et al.The clinical and pathogenetic significance of estrogen receptor-beta expression in chronic liver diseases and liver carcinoma. Cancer. 2003;98(3):529-34.
41. Jonas S, Bechstein WO, Heinze T, et al. Female sex hormone receptor status in advanced hepatocellular carcinoma and outcome after surgical resection. Surgery. 1997;121(4):456-61.
42. Zhao C, Xu L, Otsuki M, et al. Identification of a functional variant of estrogen receptor beta in an African population. Carcinogenesis 2004;25:2067–73.
43. Carruba G. Estrogens and mechanisms of prostate cancer progression. Ann N Y Acad Sci. 2006 Nov;1089:201-17.
44. Rivadeneira F, van Meurs JB, Kant J, et al. Estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor alpha (ESR1) and insulin-like growth factor I (IGF1) variants influence the risk of fracture in postmenopausal women. J Bone Miner Res. 2006;21(9):1443-56.
45. Hou L, Xu J, Gao YT, et al. CYP17 MspA1 polymorphism and risk of biliary tract cancers and gallstones: a population-based study in Shanghai, China. Int J Cancer. 2006;118(11):2847-53.
46. Berstein LM, Zimarina TS, Tsyrlina EV,et al.Genetic polymorphism of steroidogenic enzymes and steroid receptor level in tumors of the reproductive system. Vopr Onkol. 2004;50(2):169-73.
47. Nativelle-Serpentini C, Lambard S, Seralini GE, Sourdaine P.Aromatase and breast cancer: W39R, an inactive protein.Eur J Endocrinol. 2002;146(4):583-9.
48. Hayashi S-I, Watanahe J, Nakachi K, and Kawajiri K. Genetic linkage of lungcancer-associated MspI polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P4501AI gene. J Biochem. 1991,110: 407-411.
49. Hanna IH, Dawling S, Roodi N, Guengerich FP, Parl FF. Cytochrome P450 1B1 (CYP1B1) pharmacogenetics: association of polymorphisms with functional differences in estrogen hydroxylation activity.Cancer Res. 2000;60(13):3440-4.
50. Sasaki M, Tanaka Y, Kaneuchi M, et al. CYP1B1 gene polymorphisms have higher risk for endometrial cancer, and positive correlations with estrogen receptor alpha and estrogen receptor beta expressions.Cancer Res. 2003;63(14):3913-8.
51. Lee SG, Joo Y, Kim B, Chung S, Kim HL, Lee I, Choi B, Kim C, Song K.Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans.Hum Genet. 2005;116(4):319-28.
1. Sasaki Y. Does oxidative stress participate in the development of hepatocellular carcinoma? J Gastroenterol. 2006; 41(12):1135-48.
2. Cardin R, D'Errico A, Fiorentino M, et al. Hepatocyte proliferation and apoptosis in relation to oxidative damage in alcohol-related liver disease. Alcohol Alcohol. 2002; 37(1):43-8.
3. Arteel GE.Oxidants and antioxidants in alcohol-induced liver disease.Gastroenterology. 2003; 124(3):778-90.
4. Wells PG, Kim PM, Laposa RR, et al. Oxidative damage in chemical teratogenesis. Mutat Res. 1997; 396(1-2):65-78.
5. Weitzman SA, Turk PW, Milkowski DH, Kozlowski K. Free radical adducts induce alterations in DNA cytosine methylation.Proc Natl Acad Sci U S A. 1994;91(4):1261-4.
6. Pepersen DR. Alcohol, iron-associated oxidative stress, and cancer. Alcohol. 2005;35(3):243-9.
7. Lee JK, Choi EH, Lee KG, et al. Alleviation of aflatoxin B1-induced oxidative stress in HepG2 cells by volatile extract from Allii Fistulosi Bulbus. Life Sci. 2005;77(23):2896-910.
8. Korenaga M, Wang T, Li Y, Showalter LA, et al. Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Biol Chem. 2005;280(45):37481-8
9. Malgorzata Karbownik, Russel J, et al. Melatonin Attenuates Estradiol-Induced Oxidative Damage to DNA: Relevance for Cancer Prevention. Exp Biol Med. 2001; 226(7):707-12.
10. Hukkanen J, Jacob P 3rd, Benowitz NL, et al. Metabolism and disposition kinetics of nicotine. Pharmacol Rev. 2005;57(1):79-115.
11. Jungst C, Cheng B, Gehrke R, et al.Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Hepatology. 2004;39(6):1663-72.
12. Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med. 2002; 33(3):337-49.
13. Mates JM, Sanchez-Jimenez F. Antioxidant enzymes and their implications inpathophysiologic processes. Front Biosci. 1999;4:D339-45.
14. Kinnula VL, Crapo JD. Superoxide dismutases in the lung and human lung diseases.Am J Respir Crit Care Med. 2003;167(12):1600-19.
15. Elchuri S, Oberley TD, Qi W, Eisenstein RS, et al. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life.Oncogene.2005;24(3):367-80.
16. Bai J, Zhu X, Zheng X, et al. Overexpression of CuZnSOD gene suppresses the growth of hepatocellular cancer cell line HepG2. Chin Med J (Engl). 1998;111(9):789-92.]
17. Zhao Y, Xue Y, Oberley TD, et al. Overexpression of manganese superoxide dismutase suppresses tumor formation by modulation of activator protein-1 signaling in a multistage skin carcinogenesis model. Cancer Res. 2001;61(16):6082-8.
18. Van Remmen H, Ikeno Y, Hamilton M, et al. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics. 2003;16(1):29-37.
19. Laukkanen MO, Leppanen P, Turunen P, et al. EC-SOD gene therapy reduces paracetamol-induced liver damage in mice. J Gene Med. 2001;3(4):321-5.
20. Bellisola G, Casaril M, Gabrielli GB, et al. Catalase activity in human hepatocellular carcinoma (HCC). Clin Biochem. 1987;20(6):415-7.
21. Czeczot H, Scibior D, Skrzycki M, et al. Glutathione and GSH-dependent enzymes in patients with liver cirrhosis and hepatocellular carcinoma. Acta Biochim Pol. 2006;53(1):237-42.
22. Rosenblum JS, Gilula NB, Lerner RA. On signal sequence polymorphisms and diseases of distribution. Proc. Natl. Acad. Sci. 1996; 93 : 4471-4473.
23. Shimoda-Matsubayashi S, Matsumine H, Kobayashi T, et al. Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. Biochem Biophys Res Commun 1996;226:561–5.
24. Mitrunen K, Sillanpaa P, Kataja V, et al. Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk. Carcinogenesis 2001;22:827–9.
25. Christine B. Ambrosone, Jiyoung Ahn, et al. Polymorphisms in genes related to oxidative stress (MPO, MnSOD, CAT) and survival after treatment for breast cancer. Cancer Res.2005;65(3):1105-11.
26. Haojie Li, Philip W. Kantoff, et al. Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinical significant prostate cancer. Cancer Res. 2005;65(6):2498-504.
27. Hung RJ, Boffetta P, Brennan P, et al. Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis. 2004;25(6):973-8.
28. Petersen SV, Olsen DA, Kenney JM, et al. The high concentration of Arg213-->Gly extracellular superoxide dismutase (EC-SOD) in plasma is caused by a reduction of both heparin and collagen affinities. Biochem J. 2005;385(Pt 2):427-32.
29. Sandstrom J, Nilsson P, Karlsson K, et al. 10-fold increase in human plasma extracellular superoxide dismutase content caused by a mutation in heparin-binding domain. J Biol Chem. 1994;269(29):19163-6.
30. Tamai M, Furuta H, Kawashima H, et al. Extracellular superoxide dismutase gene polymorphism is associated with insulin resistance and the susceptibility to type 2 diabetes. Diabetes Res Clin Pract. 2006 Feb;71(2):140-5.
31. Forsberg L, Lyrenas L, de Faire U, et al. A common functional C-T substitution polymorphism in the promoter region of the human catalase gene influences transcription factor binding, reporter gene transcription and is correlated to blood catalase levels. Free Radic Biol Med. 2001;30(5):500-5.
32. Ahn J, Gammon MD, Santella RM, et al. Associations between breast cancer risk and the catalase genotype, fruit and vegetable consumption, and supplement use. Am J Epidemiol. 2005 Nov 15;162(10):943-52.
33. Hu YJ, Diamond AM. Role of glutathione peroxidase 1 in breast cancer: loss of heterozygosity and allelic differences in the response to selenium. Cancer Res. 2003;63(12):3347-51.
34. Lee CH, Lee KY, Choe KH, et al. Effects of oxidative DNA damage and genetic polymorphism of the glutathione peroxidase 1 (GPX1) and 8-oxoguanine glycosylase 1 (hOGG1) on lung cancer J Prev Med Pub Health. 2006;39(2):130-4
35. Ravn-Haren G, Olsen A, Tjonneland A, et al. Associations between GPX1 Pro198Leu polymorphism, erythrocyte GPX activity, alcohol consumption and breast cancer risk in aprospective cohort study. Carcinogenesis. 2006;27(4):820-5.
36. Ichimura Y, Habuchi T, Tsuchiya N, et al. Increased risk of bladder cancer associated with a glutathione peroxidase 1 codon 198 variant. J Urol. 2004;172(2):728-32.
37. Hayward LJ, Rodriguez JA, Kim JW, et al.Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis.J Biol Chem. 2002;277(18):15923-31.
38. Ukkola O, Erkkila PH, Savolainen MJ, Kesaniemi YA. Lack of association between polymorphisms of catalase, copper-zinc superoxide dismutase (SOD), extracellular SOD and endothelial nitric oxide synthase genes and macroangiopathy in patients with type 2 diabetes mellitus.J Intern Med. 2001;249(5):451-9
39. Nahon P, Sutton A, Pessayre D, et al. Genetic dimorphism in superoxide dismutase and susceptibility to alcoholic cirrhosis, hepatocellular carcinoma, and death. Clin Gastroenterol Hepatol. 2005;3(3):292-8.
40. Nahon P, Sutton A, Pessayre D, et al. Manganese Superoxide Dismutase Dimorphism and Iron Overload, Hepatocellular Carcinoma, and Death in Hepatitis C Virus-Infected Patients. Clin Gastroenterol Hepatol. 2007 Mar 1; [Epub ahead of print].
41. Ambrosone CB, Freudenheim JL, Thompson PA, et al. Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer. Cancer Res. 1999;59(3):602-6.
42. Zhou W, Thurston SW, Liu G, et al. The interaction between microsomal epoxide hydrolase polymorphisms and cumulative cigarette smoking in different histological subtypes of lung cancer. Cancer Epidemiol Biomarkers Prev. 2001;10(5):461-6.
43. Forsberg L, Lyrenas L, de Faire U, et al. A common functional C-T substitution polymorphism in the promoter region of the human catalase gene influences transcription factor binding, reporter gene transcription and is correlated to blood catalase levels. Free Radic Biol Med. 2001;30(5):500-5.
44. Lee CH, Lee KY, Choe KH, et al. Effects of oxidative DNA damage and genetic polymorphism of the glutathione peroxidase 1 (GPX1) and 8-oxoguanine glycosylase 1 (hOGG1) on lung cancer] J Prev Med Pub Health. 2006;39(2):130-4.
45. Ichimura Y, Habuchi T, Tsuchiya N, et al. Increased risk of bladder cancer associated with a glutathione peroxidase 1 codon 198 variant. J Urol. 2004;172(2):728-32.
46. Stenlund P, Tibell LA. Chimeras of human extracellular and intracellular superoxide dismutases. Analysis of structure and function of the individual domains. Protein Eng. 1999;12(4):319-25.
47. Chrobot AM, Szaflarska-Szczepanik A, Drewa G. Antioxidant defense in children with chronic viral hepatitis B and C. Med Sci Monit. 2000;6(4):713-8.
48. Sutton A, Nahon P, Pessayre D, et al. Genetic polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in patients with alcohol-induced cirrhosis. Cancer Res. 2006;66(5):2844-52.
49. Hahn LW, Ritchie MD, Moore JH. Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics. 2003; 19(3): 376-82.
50. Millstein J, Conti DV, Gilliland FD, Gauderman WJ. A testing framework for identifying susceptibility genes in the presence of epistasis.Am J Hum Genet. 2006;78(1):15-27.
1. Woychik RP, Klebig ML, Justice MJ et al. Functional genomics in the post-genome era. Mutat Res. 1998; 400(1-2):3-14.
2. From ORFeome to biology: a functional genomics pipeline. Genome Res. 2004; 14(10B):2136-44.
3. Wu J, Smith LT, Plass C, Huang TH. ChIP-chip comes of age for genome-wide functional analysis. Cancer Res. 2006; 66(14):6899-902.
4. Lee J, Nam S, Hwang SB, et al. Functional genomic approaches using the nematode Caenorhabditis elegans as a model system. J Biochem Mol Biol. 2004; 37(1):107-13.
5. Shastry BS. SNP alleles in human disease and evolution. J Hum Genet. 2002; 47(11):561-6.
6. Redon R, Ishikawa S, Fitch KR, et al. Global variation in copy number in the human genome. Nature. 2006; 444(7118):444-54.
7. Chanock S. Candidate genes and single nucleotide polymorphisms (SNPs) in the study of human disease. Dis Markers. 2001;17(2):89-98.
8. Miyamoto Y, Mabuchi A, Shi D, et al.A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat Genet. 2007; 39(4): 529-33.
9. De Gobbi M, Viprakasit V, Hughes JR, et al.A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science. 2006; 312(5777):1215-7.
10. Li X, Dumont P, Della Pietra A, et al.The codon 47 polymorphism in p53 is functionally significant. J Biol Chem. 2005; 280(25):24245-51.
11. Law AJ, Kleinman JE, Weinberger DR, Weickert CS. Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. Hum Mol Genet. 2007;16(2):129-41.
12. Dong JT, Lamb PW, Rinker-Schaeffer CW, et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science. 1995; 268(5212): 884-6.
13. Lee JH, Seo YW, Park SR, Kim YJ, Kim KK.Expression of a splice variant of KAI1, a tumor metastasis suppressor gene, influences tumor invasion and progression. Cancer Res. 2003;63(21):7247-55.
14. Liu FS, Dong JT, Chen JT,et al. KAI1 metastasis suppressor protein is down-regulated during the progression of human endometrial cancer. Clin Cancer Res. 2003;9(4):1393-8.
15. Uzawa K, Ono K, Suzuki H, et al. High prevalence of decreased expression of KAI1 metastasis suppressor in human oral carcinogenesis.Clin Cancer Res. 2002;8(3):828-35.
16. Yang X, Wei L, Tang C, Slack R, Montgomery E, Lippman M. KAI1 protein is down-regulated during the progression of human breast cancer.Clin Cancer Res. 2000;6(9):3424-9.
17. Steeg PS, Ouatas T, Halverson D, Palmieri D, Salerno M. Metastasis suppressor genes: basic biology and potential clinical use.Clin Breast Cancer. 2003;4(1):51-62.
18. Marreiros A, Czolij R, Yardley G, Crossley M, Jackson P. Identification of regulatory regions within the KAI1 promoter: a role for binding of AP1, AP2 and p53. Gene. 2003;302(1-2):155-64.
19. Gao AC, Lou W, Dong JT, Barrett JC, et al.Defining regulatory elements in the human KAI1 (CD 82) metastasis suppressor gene. Prostate. 2003;57(4):256-60.
1. Baum JK, Bookstein JJ, Holtz F, Klein EW. Possible association between benign hepatomas and oral contraceptives.Lancet. 1973 Oct 27;2(7835):926-9.
2. Yu MW, Chen CJ.Elevated serum testosterone levels and risk of hepatocellμlar carcinoma. Cancer Res. 1993 Feb 15;53(4):790-4.
3. Velazquez I, Alter BP.Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions. Am J Hematol. 2004 Nov;77(3):257-67.
4. Yu L, Nagasue N, Makino Y, Nakamura T. Effect of androgens and their manipμlation on cell growth and androgen receptor (AR) levels in AR-positive and -negative human hepatocellμlar carcinomas. J Hepatol. 1995 Mar;22(3):295-302.
5. Yu MW, Yang YC, Yang SY. Hormonal markers and hepatitis B virus-related hepatocellμlar carcinoma risk: a nested case-control study among men.J Natl Cancer Inst. 2001 Nov 7;93(21):1644-51.
6. Nakatani T, Roy G, Fujimoto N. Sex hormone dependency of diethylnitrosamine-induced liver tumors in mice and chemoprevention by leuprorelin. Jpn J Cancer Res. 2001 Mar;92(3):249-56.
7. Villa E, Baldini GM, Rossini GP, et al. Ethanol-induced increase in cytosolic estrogen receptors in human male liver: a possible explanation for biochemical feminization in chronic liver disease due to alcohol. Hepatology. 1988 Nov-Dec;8(6):1610-4.
8. Farinati F, Cardin R, Bortolami M, et al. Estrogens receptors and oxidative damage in the liver. Mol Cell Endocrinol. 2002 Jμl 31;193(1-2):85-8.
9. Villa E, Colantoni A, Grottola A, et al. Variant estrogen receptors and their role in liver disease. Mol Cell Endocrinol. 2002 Jμl 31;193(1-2):65-9.
10. Feigelson HS, Shames LS, Pike MC, et al. Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res. 1998 Feb 15;58(4):585-7.
11. Chen J, Lipska BK, Halim N, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet. 2004 Nov;75(5):807-21. Epub 2004 Sep 27.
12. Yin PH, Lee HC, Chau GY, et al. Polymorphisms of estrogen-metabolizing genes and riskof hepatocellμlar carcinoma in Taiwan females.Cancer Lett. 2004;212(2):195-201.
13. Llovet JM. Updated treatment approach to hepatocellμlar carcinoma. J Gastroenterol. 2005 Mar;40(3):225-35.
14. De Maria N, Manno M, Villa E. Sex hormones and liver cancer. Mol Cell Endocrinol. 2002 ; 193(1-2):59-63.
1. Huang YS, Chern HD, Wu JC, et al. Polymorphism of the N-acetyltransferase 2 gene, red meat intake, and the susceptibility of hepatocellμlar carcinoma. Am J Gastroenterol. 2003;98(6):1417-22.
2. Agundez JA. Cytochrome P450 gene polymorphism and cancer. Curr Drug Metab. 2004;5(3):211-24.
3. Yeo AE, Tanaka Y, Furuta T. Interleukin 1 beta gene polymorphism and hepatitis C virus-related hepatocellμlar carcinoma. Hepatology. 2003;38(1):267-8; author reply 268-9.
4. Petersen DR. Alcohol, iron-associated oxidative stress, and cancer. Alcohol. 2005;35(3):243-9.
5. Lee JK, Choi EH, Lee KG, et al. Alleviation of aflatoxin B1-induced oxidative stress in HepG2 cells by volatile extract from Allii Fistμlosi Bμlbus. Life Sci. 2005;77(23):2896-910.
6. Korenaga M, Wang T, Li Y, Showalter LA, et al. Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Biol Chem. 2005;280(45):37481-8.
7. Kyoji Moriya, Kiyotaka Nakagawa, Tomofumi Santa, et al. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis.Cancer Res. 2001;61(11):4365-70.
8. Elchuri S, Oberley TD, Qi W, Eisenstein RS, et al. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life.Oncogene. 2005;24(3):367-80.
9. Jungst C, Cheng B, Gehrke R, et al. Oxidative damage is increased in human liver tissue adjacent to hepatocellμlar carcinoma.Hepatology. 2004;39(6):1663-72.
10. Mitrunen K, Sillanpaa P, Kataja V, et al. Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk. Carcinogenesis. 2001;22(5):827-9.
11. Czeczot H, Scibior D, Skrzycki M, et al. Glutathione and GSH-dependent enzymes in patients with liver cirrhosis and hepatocellμlar carcinoma. Acta Biochim Pol. 2006;inpress.
12. Liaw KY, Lee PH, Wu FC, et al. Zinc, copper, and superoxide dismutase in hepatocellμlar carcinoma. Am J Gastroenterol. 1997;92(12):2260-3
13. Ahn J, Gammon MD, Santella RM, et al. Associations between breast cancer risk and the catalase genotype, fruit and vegetable consumption, and supplement use. Am J Epidemiol. 2005;162(10):943-52.
14. Ambrosone CB, Ahn J, Singh KK, et al. Polymorphisms in genes related to oxidative stress (MPO, MnSOD, CAT) and survival after treatment for breast cancer. Cancer Res. 2005;65(3):1105-11
15. Hamanishi T, Furuta H, Kato H, et al. Functional variants in the glutathione peroxidase-1 (GPx-1) gene are associated with increased intima-media thickness of carotid arteries and risk of macrovascμlar diseases in japanese type 2 diabetic patients.Diabetes. 2004;53(9):2455-60