Association of IL-6 polymorphisms with hepatocellular carcinoma risk: evidences from a meta-analysis

The associations between IL-6 gene single nucleotide polymorphisms (SNPs) and risk of hepatocellular carcinoma (HCC) are controversial. We performed a meta-analysis to provide more credible evidence. We searched for relevant studies published up to 2013 by performing an efficient searching strategy. Odds ratios (OR) with 95 % confidence interval (95 % CI) was used to estimate the strength of the associations between IL-6 polymorphisms and HCC risk. We identified eight case–control studies involving 1,448 HCC cases and 3,160 controls. Our estimation specifically focused on two SNPs of the IL-6 gene, ?174 G/C and ?572 G/C. The combined results showed that association between IL-6-174 G/C polymorphism and risk of HCC was significant under additive model (CC vs. GG: OR 0.36; 95 % CI, 0.16, 0.85) and recessive model (GG+CG vs. CC: OR 2.82; 95 % CI 1.26, 6.28). However, the IL-6-572 G/C polymorphism was not associated with HCC risk. In conclusion, IL-6-174 G/C, but not ?572 G/C polymorphism could be a candidate for susceptibility to HCC. However, the results should be cautiously interpreted due to the limited number of the included studies.     

High expression of IL-17 and IL-17RE associate with poor prognosis of hepatocellular carcinoma

Background

Hepatocellular carcinoma (HCC) is a typical malignancy in a background of chronic inflammation. Th17 cells (a major source of IL-17) constitute crucial components of infiltrating inflammatory/immune cells in HCC and can amplify inflammatory response via binding to interleukin-17 receptor (IL-17R). Thus, we investigated the expression and clinical significance of IL-17 and IL-17 receptor family cytokines in HCC.

Methods

The expression and prognostic value of IL-17 and IL-17R (A-E) were examined in 300 HCC patients after resection. Six Th17 associated cytokines in serum (n = 111) were quantified using enzyme-linked immunosorbent assays. Phenotypic features of IL-17⁺ CD4⁺ T cells were determined by flow cytometry analysis.

Results

High expression of intratumoral IL-17 and IL1-7RE were significantly associated with poorer survival (p = 0.016 and <0.001, respectively) and increased recurrence (both P < 0.001) of HCC patients. Moreover, intratumoral IL-17, individually or synergistically with IL-17RE, could predict HCC early recurrence and late recurrence. Also, peritumoral IL-17RE showed the prognostic ability in HCC (P < 0.001 for OS/TTR). Furthermore, expression levels of Th17 associated cytokines including IL-6, -22, -17R and TNF-α were increased in serum of HCC patients compared to haemangioma patients. Importantly, activated human hepatic stellate cells induced in vitro expansion of IL-17⁺ CD4⁺ T cells.

Conclusions

High expression of IL-17 and IL-17RE were promising predictors for poor outcome of HCC patients. The protumor power of IL-17 producing CD4⁺ T cells was probably involved in the crosstalk with different types of inflammatory/immune cells in HCC.     

IL-27基因多态性和血清 IL-27 p28水平与骨肉瘤风险相关性分析

目的：评估IL-27基因多态性和血清IL-27p28水平与骨肉瘤风险的相关性。方法对比研究160例骨肉瘤患者（研究组）和250例健康患者（对照组）。 IL-27基因-964 A／G，2905 T／G，和4730 T／C多态性采用聚合酶链反应-限制性片段长度多态性测定。酶联免疫吸附试验检测血清中IL-27p28的水平。结果与对照组相比，骨肉瘤患者血清IL-27p28水平显著降低（P＜0．01）。Ⅲ～Ⅳ期骨肉瘤患者血清IL-27p28水平低于Ⅰ～Ⅱ期患者（P＜0．05）。同样，转移患者的血清IL-27p28水平低于非转移患者（ P＜0．05）。 IL-27-964 A／G，2905 T／G，4730 T／C的基因型和等位基因频率与骨肉瘤风险无相关性（ P＞0．05）。分层分析也未能显示-964 A／G，2905 T／G，和4730 T／C多态性与临床分期和骨肉瘤的转移存在相关性（P＞0．05）。结论血清IL-27p28低水平可能与骨肉瘤进展有关，但IL-27基因-964 A／G，2905 T／G，和4730 T／C多态性和它们的单倍型不与骨肉瘤的风险相关联。     

Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in caucasian women.

PURPOSE: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown. EXPERIMENTAL DESIGN: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [-889 C/T polymorphism of the IL1alpha gene (IL1A), -511 C/T polymorphism of the IL1beta promoter (IL1B promoter), a polymorphism of IL1beta exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the -174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. RESULTS: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. CONCLUSIONS: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the -174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.     

Interferon-γ and Interleukin-10 Gene Polymorphisms are not Predictors of Chronic Hepatitis C (Genotype-4) Disease Progression

Immunoregulatory cytokines have an influence on hepatitis C virus (HCV) infection outcome. This studyaimed to determine whether single nucleotide polymorphisms (SNP) in IFN- γ and IL-10 genes are associatedwith susceptibility and/or are markers of prognosis regarding chronic hepatitis C outcomes. IFN γ (+874T/A)and IL-10 (-1082G/A) genotypes were determined in 75 HCV genotype 4 patients with different disease severities(chronic hepatitis, n=25, liver cirrhosis and hepatocellular carcinoma (HCC) on top of liver cirrhosis, n=50)and 25 healthy participants using allele-specific polymerase chain reaction. No statistical differences in alleleor genotype distributions of IFN γ and IL-10 genes were detected between patients and controls or betweenpatientgroups. No significant difference in the frequency of IL-10 SNP at position -1082 or IFN-γ at position+874T/A was found between chronic HCV genotype 4 and with progression of disease severity in liver cirrhosisor HCC. In conclusion; interferon-γ and interleukin-10 gene polymorphisms are not predictors of diseaseprogression in patients with chronic hepatitis C (Genotype-4).     

Influence of plasminogen activator inhibitor-1 (SERPINE1) 4G/5G polymorphism on circulating SERPINE-1 antigen expression in HCC associated with viral infection

Hepatocarcinogenesis is heavily influenced by chronic hepatitis B (HBV) and C (HCV) infection. Elevated levels of plasminogen activator inhibitor-1 (SERPINE1/PAI-1) have been reported in patients with hepatocellular carcinoma (HCC) associated with viral infection. The gene encoding SERPINE1 is highly polymorphic and the frequently associated 4/5 guanosine (4G/5G) polymorphism in the gene promoter may influence its expression. Here, we investigated the distribution of genotypes and the frequency of alleles of the 4G/5G polymorphism in patients with HCC, the influence of the 4G/5G polymorphism on plasma SERPINE1 levels and its association with viral infection. A total of 75 patients with HCC were enrolled: 32 (42.6%) were HBV(+)/HCV(+), 11 (14.6%) were only HCV(+), and 32 (42.6%) were negative for both viruses. A control group of healthy donors was also enrolled (n=50). SERPINE1 plasma concentrations were determined by ELISA and the detection of the promoter 4G/5G polymorphism was performed by an allele-specific PCR analysis. We found that the frequency of both the 4G/4G genotype (p=0.02) and the 4G allele (p=0.006) were significantly higher in patients with HCC compared to the control group, and particularly higher in patients with HCC co-infected with HBV(+)/HCV(+) than in those with no viral infection. We also found that patients with the 4G/4G genotype had significantly higher plasma SERPINE1 protein levels when compared with patients with the 4G/5G or 5G/5G genotype (p<0.001). Differences in frequency of 4G allele and genetic variability of 4G/5G SERPINE1 polymorphism with a higher level of SERPINE1 protein in patients with HCC with HBV(+)/HCV(+) than those without infection, suggest the presence of two distinct pathogenic mechanisms in hepatocarcinogenesis, depending on the etiology.     

Interleukin-6-174 Promoter Polymorphism and Susceptibility to Hepatitis B Virus Infection as a Risk Factor for Hepatocellular Carcinoma in Iran

Background: Hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC). Cytokines play an important role in the regulation of immune responses and defense against viral infections. Human interleukin 6 (IL6) is a multifunctional cytokine that participates in these processes. Objective: The aim of this study was to assess the IL6-174 gene polymorphism in patients with chronic hepatitis B virus (HBV) infection as compared with healthy controls in an Iranian population. Materials and Methods: Totals of 297 HBV patients and 368 control individuals were evaluated. Genomic DNA was extracted from peripheral blood and the SSP-PCR (sequence specific primer-polymerase chain reaction) method was applied for genotyping. Results: The frequencies of genotypes C/C, G/G and C/G in HBV cases were 4.7%, 34.3%, 60.9% and in controls were 12.8%, 39.7% and 47.6%, respectively. The frequencies of G and C allele in patients and controls were 78.1%, 21.9% and 67.4%, 32.6 % respectively. There was a significant difference in the frequencies of G/G genotype (CI=1.8-7.1, OR=3.47, P=0.00001) and G allele (CI=1.34-2.23, OR=1.72, P=0.0001) between HBV patients and the control group. Conclusions: These findings suggest that the IL6-174 C/G genotype and the G allele are strongly associated with susceptibility to HBV infection. Demographic information showed that most of the subjects were male (74.4%). According to high frequency of G/G genotype in male participants (63.1%) men probably are more susceptible to hepatitis than women.     

Allo-HSCT患者血浆IL-17和IL-23与aGVHD相关性分析

目的：异基因造血干细胞移植（Allo—HscT）患者移植前后血浆中IL-17、IL-23浓度与急性移植物抗宿主病（acute graft versus host disease,aGVHD）相关性分析。方法：采用双夹心酶联免疫吸附法（ELISA）检测患者血清中IL-17和IL-23浓度,采用逆转录聚合酶链反应法（ReahimePCR）检测IL-17mRNA和IL-2mRNA相对表达量。结果：1）移植后aGVHD阴性组和aGVHD阳性组患者在性别、年龄、疾病类型、组织类型和预处理方案差异均无统计学意义,P〉0．05。2）各组血浆中IL-17与IL-23浓度检测结果,aGVHD阳性组IL-17的浓度为（330．0±11．5）ρg／mL,显著高于对照组的（109．6±7．6）ρg／mL和aGVHD阴性组的（243．1±16．4）ρg／mL,P值均〈0．00l;aGVHD阳性组IL-23的浓度为（250．6±14．3）ρg／mL,显著高于对照组的（101．5±9．6）ρg／mL和aGVHD阴性组的（111．0±16．3）ρg／mL,P值均〈0．001。3）aGVHD阳性组血浆中IL-17与IL23浓度检测结果,aGVHD发生当天血浆中IL-17的浓度为（330．0±11．5）Dg／mL,IL-23的浓度为（250．6±14．3）9g／mL,显著高于aGVHD发生前2周和aGVHD发生后1、2和3周IL-17和IL-23的浓度,P值均〈0．05。IL-17、IL-23的浓度在aGVHD发生当天达到高峰,随着症状的控制,逐渐下降。4）aGVHD阳性患者IL-17mRNA的相对表达量为,3．232±1．137,显著高于对照组的1．432±0．954和aGVHD阴性组的1．672±0．896,P值均〈0．001;aGVHD阳性患者IL-23mRNA的相对表达量为2．142±1．194,显著高于对照组的1．242±0．752和aGVHD阴性组的1．496±0．653,P值均〈0．001。结论：A110HSCT后血浆中IL-17、IL-23与aGVHD的发生呈正相关,动态检测allo—HSCT后IL—17和IL-23浓度的变化,可能为临床上预测或诊断aGVHD的发生提供预警或依据。     

IL-6 Impairs the Activity of Vitamin D3 in the Regulation of Epithelial-Mesenchymal Transition in Triple Negative Breast Cancer

Objective: The present study aimed to investigate the possible role of IL-6 and 1α,25-dihydroxyvitamin D3 (1,25D)signaling in epithelial-mesenchymal transition (EMT) and stemness in triple-negative breast cancer (TNBC) cell line.Methods: TNBC cell line, HCC 1806, was treated with IL-6 and 1,25D for three and six days. Also, the role of vitaminD receptor (VDR) was studied by transfection of TNBC cell line with VDR gene and transfection efficiency was assessedusing Human VDR enzyme-linked immunosorbent assay (ELISA). Changes in E-cadherin gene expression wereanalyzed by quantitative real-time PCR (qRT-PCR). Also, changes in CD44+ cells were analyzed by flow cytometry.Finally, morphological changes were investigated by light microscopy after 6 days. Results: Treatment of HCC1806cells with IL-6 has no significant effect either on E-cadherin gene expression or CD44+ cells, (p > 0.05). However,E-cadherin gene expression was significantly up-regulated after treatment with 1,25D for 6 days, (p < 0.05). Also, CD44+cells were significantly reduced after treatment with 1,25D either for 3 or 6 days, (p < 0.05). Transfection of TNBCcell line with VDR gene significantly up-regulated VDR protein expression, (p < 0.05). In addition, overexpression ofVDR in TNBC cells and treatment with 1,25D significantly up-regulated E-cadherin gene expression, (p < 0.05) andreduced CD44+ cells, (p < 0.05). Moreover, transfection with VDR and treatment with a combination of 1,25D andIL-6 significantly down-regulated E-cadherin gene expression and increased CD44+ cells compared with transfectedcells with VDR treated with 1,25D alone, (p < 0.05). No significant morphological changes were observed in treatedcells, 6 days post-treatment. Conclusion: The presence of IL-6 in the breast tumor microenvironment may impair theactivity of vitamin D3 signaling, limiting its anti-tumor effects in TNBC.     

白细胞介素-10启动子区基因多态性与非霍奇金淋巴瘤相关性的研究

目的：探讨中国汉族人群白细胞介素－10基因（IL－10）启动子区－1082G／A、－819T／C和－592A／C基因多态性与非霍奇金淋巴瘤（NHL）发病的关系。方法：采用聚合酶链－限制性片段长度多态技术检测512例NHL患者和500名健康对照者IL－10启动予区－1082、－819和－592位点的基因型。结果：NHL组IL－10—1082位点AA、GA、GG基因型频率分别为85．7％、14．3％和0,对照组分别为88．8％、11．2％和0,两组相比差异无统计学意义,P〉0．05。－819位点与～592位点基因型具有高度连锁,－819TT／－592AA、819TC／～592AC和－819CC／－592CC基因型在NHI,组分别为45．9％、41．2％和12．9％,对照组分别为48．8％、40．8％和10．4％,两组相比差异无统计学意义,P〉0．05。对NHL亚型分析显示,各位点基因型在弥漫性大B细胞淋巴瘤（DLBCL）和滤泡性淋巴瘤（FL）病例组中与对照组相比,差异均无统计学意义,P〉0．05。单体型分析发现,上述位点具有4种单体型ATA、ACC、GCC和GTA,各单体型在NHL及其各亚型组与对照组之间的分布差异无统计学意义,P〉0．05。结论：中国汉族人群中IL－10启动子区－1082、－819和－592位点基因多态性及其单体型分布与NHL发病无相关性。     

The involvement of genetic polymorphism of IL-10 promoter in non-small cell lung cancer

STUDY OBJECTIVES: Interleukin-10 (IL-10) is mainly an anti-inflammatory cytokine produced by a number of cells including normal and neoplastic cells and has been implicated in autoimmunity, transplantation tolerance and tumorigenesis. Inter-individual variations in IL-10 production were genetically contributed to polymorphisms within IL-10 promoter region. The aim of this study was to determine whether polymorphisms in the IL-10 gene promoter were involved in predisposing an individual to non-small cell lung cancer (NSCLC). PATIENTS: A total of 154 patients with non-small cell lung cancer were recruited into this study, together with 205 age- and gender-matched healthy smokers acting as control subjects. MEASUREMENTS: Polymorphisms of sites within the promoter region of IL-10 gene were analyzed using polymerase chain reaction-restriction fragment length polymorphism technique on genomic DNA isolated from peripheral lymphocytes. The validity of this technique was proven by direct sequencing of polymerase chain reaction products. Statistical analyses were conducted to explore the contribution of polymorphism of IL-10 promoter to the susceptibility to NSCLC. RESULTS: The distribution frequencies of genotypes of IL-10-1082, -819 and -592 were significantly different between NSCLC patients and controls. Pearson chi2 analysis showed that the frequency for IL-10-1082 G allele, IL-10-819C allele and IL-10-592C allele was independently higher in NSCLC patient group than that in the control group. Higher odds ratios (ORs) for NSCLC were seen for individuals with G allele of IL-10-1082 [OR=5.26, 95% CI 2.65-10.4, p<0.0001], C allele of IL-10-819 [OR=1.57, 95% CI 1.15-2.16, p=0.005], C allele of IL-10-592 [OR=1.59, 95% CI 1.15-2.19, p=0.005]. CONCLUSION: The polymorphisms of IL-10 genes were significantly associated with the occurrence of NSCLC.     

Association of IL-6 -174G>C and -572G>C Polymorphisms with Susceptibility to Cervical Cancer and Ovarian Cancer

Background: During the past decades, the expansion of molecular development has had a key role in understanding the basis of gynecological cancer. Interleukin-6 (IL-6) is known to be involved in the pathogenesis of different cancers. Here, we evaluated the association of IL-6 -174G>C and -572 G>C polymorphisms with susceptibility to cervical and ovarian cancers in an Iranian population. Methods: A total of 131 cases with ovarian cancer, 124 cases with cervical cancer and 140 healthy subjects were enrolled to the study. DNA was extracted from peripheral blood cells of subjects to genotype the IL-6 -174G>C and -572 G>C polymorphisms by amplification refractory mutation system (RFLP) polymerase chain reaction (PCR). Results: There was a significant association of IL-6 -174G>C CC genotype (OR= 3.231, 95% CI: 1.130-9.239, p=0.029) and C allele (OR = 1.915; 95%CI: 1.266-2.896, p=0.002) with an increased risk of ovarian cancer. Moreover, the IL-6 -174G>C CC genotype (OR= 3.162, 95% CI: 1.094-9.141, p=0.034) and C allele (OR = 1.724; 95%CI: 1.129-2.633, p=0.012) was associated with increased risk of cervical cancer. Conclusions: This study showed that the IL-6 -174G>C polymorphism was associated with ovarian cancer and cervical cancer risk. However, IL-6 -572 G>C polymorphism was not associated.     

XRCC1 Gene Polymorphism Increases the Risk of Hepatocellular Carcinoma in Egyptian Population

Several major risk factors for hepatocellular carcinoma (HCC) have been identified, including chronic infection of hepatitis B virus (HBV) and hepatitis C virus (HCV). Nevertheless, only a fraction of infected patients develops HCC during their lifetime suggesting that genetic factors might modulate HCC development. X-ray repair cross complementing group1 (XRCC1) participates in the repair pathways of DNA. Aim: to investigate the association between XRCC1 gene polymorphism and HCC in Egyptian chronic hepatitis C patients. Methods: This study was assessed on 40 patients with HCC secondary to chronic HCV infection who were compared to 20 cirrhotic HCV patients and 40- age and gender- matched healthy control group. After collection of relevant clinical data and basic laboratory tests, c.1517G>C SNP of XRCC1 gene polymorphism was performed by (PCR-RFLP) technique. Results: A statistically higher frequency of XRCC1 (CC, GC) genotypes and increased (C) allele frequency in patients with HCC was found in comparison to cirrhotic HCV patients as well as control group. In addition, patients with the XRCC1 (CC, GC) genotypes had significantly higher number and larger size of tumor foci and significantly higher Child Pugh grades. Multivariate analysis showed that the presence of c.1517G>C SNP of XRCC1 gene is an independent risk for the development of HCC in chronic HCV patients with 3.7 fold increased risk of HCC development. In conclusion: XRCC1 gene polymorphism could be associated with increased risk of HCC development in chronic HCV Egyptian patients.     

Role of IL-18 Gene Promoter Polymorphisms,Serum IL-18 Levels,and Risk of Hepatitis B Virus-related Liver Disease in the Guangxi Zhuang Population: a Retrospective Case-Control Study

Background: The aim of this study was to assess the relationship between IL-18 gene polymorphismsand HBV-related diseases and whether these polymorphisms influence its expression in the Guangxi Zhuangpopulation. Materials and Methods: We enrolled 129 chronic HBV infected (CHB) patients, 86 HBV-related livercirrhosis (LC) patients and 160 healthy controls in our study. Polymerase chain reaction-restriction fragmentlength polymorphism methods were used to detect IL-18 gene -607C/A, -137G/C polymorphisms, and an ELISAkit was employed to determine serum IL-18 levels. Results: No correlation was found between the -607C/Apolymorphism and risk of HBV-related disease. For the -137G/C polymorphism, the GC genotype and C allelewere associated with a significantly lower risk of CHB (95%CI: 0.32-0.95, p=0.034 and 95%CI: 0.35-0.91,p=0.018) and HBV-related LC (95%CI: 0.24-0.89, p=0.022 and 95%CI: 0.28-0.90, p=0.021). A similar decreasedrisk was also found with the A-607C-137 haplotype. With respect to IL-18 expression, it was significantly lowerin both patient groups, but no association was noted between the two polymorphisms in the IL-18 gene and itsexpression. Conclusions: Our study indicated that the -137C allele in the IL-18 gene may be a protective factorfor HBV-related disease, and serum IL-18 level may be inversely associated with CHB and HBV-related LC.     

Role of IL-12p40 in cervical carcinoma

Background:

Previously, we have shown that low IL-12p40 mRNA expression by cervical cancer cells is associated with a poor survival of cervical cancer patients. As IL-12p40 is both a subcomponent of interleukin (IL)-12 and IL-23, the aim of this study was to elucidate the role of IL-12p40 in cervical cancer.

Methods:

We have measured the expression of IL-23p19 mRNA, IL-12p35 mRNA and IL-12p40 mRNA using mRNA in situ hybridisation. The IL-1 and IL-6 were measured by immunohistochemistry.

Results:

As IL-23 is a component of the IL-17/IL-23 pathway, a pathway induced by IL-1 and IL-6 in humans, we have studied IL-1 and IL-6 expression. Only a high number of stromal IL-6-positive cells was shown to associate with poor disease-specific survival. The worst disease-specific survival was associated with a subgroup of patients that displayed a high number of IL-6-positive cells and low IL-12p40 expression (P<0.001). Both a high number of IL-6-positive cells and a high number of IL-6-positive cells, plus low IL-12p40 expression were shown to be clinicopathological parameters independent of lymph node metastasis, parametrial involvement and Sedlis score (P=0.009 and P=0.007, respectively).

Conclusion:

Our results with IL-6 and IL-12p40 are in accordance with the hypothesis that the IL-17/IL-23 pathway has a suppressive role in cervical cancer.     

Tumor necrosis factor-alpha -308G/A polymorphism and risk of hepatocellular carcinoma in hepatitis C virus-infected patients

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.     

MIF、IL-17、IL-10在肝细胞癌组织中的表达及临床意义

目的 检测肝细胞癌（HCC）组织中巨噬细胞移动抑制因子（MIF）、白细胞介素（IL）-17和IL-10的表达,并探讨其临床意义。方法 收集2010年9月至2013年3月52例术后HCC组织及其周围肝硬化组织和20例正常肝脏组织,采用免疫组化染色法检测各组织中MIF、IL-17和IL-10蛋白的表达,并分析其表达与HCC临床病理特征的关系。结果 52例HCC组织中MIF、IL-17和IL-10蛋白的阳性表达率分别为78.8％、76.9％、28.8％,相应的癌旁肝硬化组织中分别为75.0％、73.0％、32.7％,20例正常肝组织中分别为20.0％、25.0％、70.0％。HCC和肝硬化组织中MIF和IL-17的阳性表达率高于正常肝组织,而IL-10的阳性表达率则低于正常肝组织,差异均有统计学意义（P＜0.05）。HCC组织中MIF、IL-17、IL-10表达与肿瘤直径、分化程度相关（P＜0.05）,而与年龄、性别、癌栓形成及Child Pugh分级均无关;HCC组织不同MIF、IL-17、IL-10表达与1年生存率相关。结论 MIF、IL-17及IL-10的表达与HCC发生、发展及预后密切相关。     

Direct Relationship between Interleukin-10 Gene Polymorphism and Hepatocellular Carcinoma Complicated by Direct Acting Antiviral Treatment of Hepatitis C Virus

Objective: This study aimed to assess the correlation between the genotyping of interleukin-10 (IL-10 polymorphism rs 1800871) and the incidence hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV) treated with direct acting antivirals (DAAs). Method: For 200 patients with HCV infection who completed DAA treatment and followed up for 1 year, IL-10 polymorphism SNP(-819) rs 1800871 analysis was conducted via real time polymerase chain reaction. During the follow-up period, 100 patients who developed HCC were selected and compared with 100 patients who did not develop any complications. Results: The studied patients were divided into two groups according to the incidence of complications after completion of DAA treatments. During the follow-up, 100 patients with HCV infection who developed HCC were selected and compared with 100 patients with HCV infection who did not develop any complications (positive control group). For the HCC group (n = 100), the mean age was 58.1 ± 6.4 years, with 92.7% being male and 7.3% being female; 91% had cirrhosis, 10% had lymphadenitis, 75% had splenomegaly, and 17% had ascites. In the positive control group (n = 100), mean age was 46.3 ± 9.4 years, with 68% being male and 32% being female; 20% had cirrhosis, 12% had splenomegaly, and 4.2% had ascites. The results demonstrated that sofosbuvir (SOF) + daclatasvir + ribavirin regimen was the most prevalent drug treatment for patients with HCC (72%), while SOF + Simeprevir was the most safe treatment for HCV infection among patients with HCC (2%). CT genotype was the most common genotype in the HCC group (56%), among different drug regimen (67.8%). T allele was the most prevalent in HCC group (61%), while the C allele was the least prevalent (39%). Conclusion: IL-10 genotyping may help in selecting the safest and most accurate drug regimen according to the safest genotype response relationship and follow-up of genotype resistance.     

Association between IL-18 -607 C/A Polymorphism and the Risk of Prostate Cancer: A Meta-Analysis of Case-Control Studies

Background: Accumulating evidence shows that cytokines play an important role in the proliferation of prostatecancer. This research is trying to determine that IL-18 -607 C/A polymorphism confers susceptibility to prostate cancer.Methods: Meta-analysis was used to collect data. The relevant studies were identified through a comprehensive searchfrom PubMed, Excerpta Medica Database (EMBASE), Web of Science, and Chinese Biomedical Literature Database(CBM) to obtain related studies published up to December 6, 2017. The association between interleukin (IL)-18 -607 C/Apolymorphism and prostate cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals(CIs). Results: Nine case-control studies from 6 articles were eventually identified. In the overall population, there is asignificant association between IL-18 -607 C/A polymorphism and prostate cancer risk in recessive (CC versus CA/AA:OR = 0.20, 95% CI = 0.15-0.27, P = 0.000) or dominant (CC/CA versus AA:OR = 0.42, 95% CI = 0.30–0.57, P = 0.000)models. In the sub-group analysis according to ethnicity, for Asians, IL-18 -607 C/A polymorphism was significantlyassociated with prostate cancer in allele contrast (C versus. A: OR=0.82, 95%CI=0.70-0.97, P=0.019), homozygote(CC versus. AA: OR=0.68, 95%CI=0.50-0.92, P=0.013), recessive (CC versus. CA/AA: OR=0.19, 95%CI=0.13-0.27,P=0.000), and dominant (CC/CA versus. AA: OR=0.37, 95%CI=0.28-0.48, P=0.000) models, for Caucasians, IL-18-607 C/A polymorphism was significantly associated with prostate cancer risk in allele contrast (C versus. A: OR=1.27,95%CI=1.02-1.58, P=0.033), homozygote (CC versus. AA: OR=1.86, 95%CI=1.19-2.91, P=0.007) and recessive (CCversus. CA/AA: OR=0.25, 95%CI=0.19-0.33, P=0.000) models. Conclusion: This meta-analysis has shown that IL-18-607 C/A polymorphism contributes to a decreased risk of prostate cancer risk in the Asian population but an increasedrisk in the Caucasian population.     

Relation between cytokine promoter gene polymorphism and toxicity of 5-fluorouracil plus cisplatin chemotherapy

Variability in the efficacies and toxicities of anticancer agents is a major problem. We hypothesized that polymorphisms in cytokine gene promoters may underlie genetic susceptibility to chemotherapy-induced toxicities in the Japanese. DNA was extracted from 100 patients undergoing 5-fluorouracil plus cisplatin chemotherapy. We used a case-only design to evaluate the relation between toxicities and cytokine promoter gene polymorphisms. The following polymorphisms were genotyped: tumor necrosis factor (TNF)-alpha-1031T/C, interleukin (IL)-1beta-511C/T, IL-6-634C/G, IL-10-819T/C, IL-18-137G/C, macrophage migration inhibitory factor -173G/C, and 86-basepair variable numbers of tandem repeat in intron 2 of the IL-1 receptor antagonist. The frequency of the IL-6-634 GC and GG genotypes was significantly higher in patients with grades 1-4 leukopenia (P=0.003; Crude-odds ratios (Cr-OR) =4.0), neutropenia (P=0.0051; Cr-OR=3.6), or thrombocytopenia (P<0.0001; Cr-OR=6.1) than in patients without these toxicities. Similarly, the frequency of the IL-1beta-511 TC and TT genotypes and the frequency of the TNF-alpha-1031 TT genotype were significantly higher in patients with grades 1-4 thrombocytopenia (P=0.015; Cr-OR=2.9) and stomatitis (P=0.02; Cr-OR=3.1), respectively. Multivariate analysis of factors such as age, sex, disease type, purpose of the chemotherapy, use of radiotherapy, and cytokine promoter gene polymorphisms showed polymorphisms to be significant predictors of toxicity. Our results suggest that polymorphisms in cytokine gene promoters may be associated with susceptibilities to leukopenia, neutropenia, thrombocytopenia and stomatitis in patients treated with 5-fluorouracil plus cisplatin.