Impact of interleukin-18 polymorphisms-607 and -137 on clinical characteristics of renal cell carcinoma patients
Introduction
Renal cell carcinoma (RCC) is the most common renal tumor and represents 2%–3% of all malignancies. RCC is two fold more frequent in men than in women, and the highest RCC incidence is observed in the sixth decade [1]. Considerable evidence has been published over the past few years linking increased tumor risk with inflammation, and clinical and experimental studies have associated tumor progression with the upregulation of proinflammatory molecules, especially during late stages of the disease [2], [3]. Chronic inflammation, alongside the intrinsic properties of premalignant cells and other determinants, may be one of the driving forces of tumor initiation and promotion. Thus, numerous mediators released in dysregulated chronic inflammation were found to promote cell growth and invasion, inducing mutagenesis and increasing angiogenicity [4]. In this context, genetic polymorphisms in different inflammatory cytokine have been associated with cancer risk and the growth or invasiveness of RCC and others types of tumor [5], [6], [7].
Interleukin (IL)-18 was discovered as an interferon (IFN)-γ–inducing factor. IL-18 is a member of the IL-1 family, and its receptor belongs to the IL-1 receptor family. When IL-18 binds to IL-18Rα, IL-18Rβ transduces its signal to stimulate the mitogen-activated protein kinase pathway, which is involved in producing IFN-γ [8]. IL-18 can activate immune cells, with or without IL-12 [9], promoting the activation and proliferation of T and natural killer cells [10], [11]. Transformed cells and tumors are effectively eliminated by IL-18-mediated activation of immune cells such as cytotoxic T cells and natural killer cells [12]. Intratumoral injection of IL-18 DNA enhances IFN-γ production, causes regression of liver tumor and has been proposed as a cancer treatment [13]. B7-1 costimulatory molecule in combination with IL-18 was used by Cho et al. against malignant skin tumors, including melanoma [14].
However, IL-18 can also promote tumor cells, as evidenced by the elevated expression of IL-18 in tumor cells [15], [16]. IL-18 expression was also elevated in the tumor versus nontumor area in gastric cancer patients and was related to distant metastasis [17]. Higher IL-18 levels were found in serum from breast cancer patients with than without metastasis and were proposed as an important marker of breast cancer progression [18]. It also enhances immune escape by promoting the expression of Fas ligand in tumor cells and downregulating major histocompatibility complex class I expression [19], [20].
We have described previously that the proangiogenic function of other interleukins (e.g., IL-10) [6] could have an important role in RCC growth and metastasis. IL-18 plays a major role in angiogenesis. The induction of IL-18 by hypoxia or inflammatory cells augments the expression of hypoxia-inducible factor (HIF)-1α and tumor cell metastases [21]. IL-18 proangiogenic functions are essential for tumor growth [22].
Hence, IL-18 can stimulate the immune system against tumor cells but can also induce angiogenesis, metastasis, proliferation, and immune escape [23]. The objective of this study was to determine the role in RCC of two single-nucleotide polymorphisms (SNPs) in the IL-18 promoter region, which are known to alter IL-18 promoter activity. Allele C at -607 position and allele G at -137 position (-607 A/C [rs1946518] and -137 G/C [rs187238], respectively) are correlated with higher serum levels of IL-18 [24].
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Patients
The study included 158 patients diagnosed with clear-cell renal carcinoma (RCC) at the Department of Urology of Virgen de las Nieves Hospital between 1997 and 2008. All patients had undergone radical or partial nephrectomy. The mean age was 60 years (range, 23–84 years). Clinicopathological characteristics are shown in Table 1. Two consulting pathologists retrospectively and independently reviewed the hematoxylin and eosin–stained tissue slides according to the World Health Association
IL-18 genotypes and cancer risk
This case-control study revealed similar frequencies in the distribution of IL-18-137 and -607 polymorphisms between healthy controls and patients with RCC (p = 0.1 and p = 0.3, respectively, for allele frequencies). Table 2 presents the genotype distributions and statistical analysis. The observed genotype frequencies were in accordance with Hardy–Weinberg equilibrium. The allele distribution and haplotypes of the control group were previously published [26] and were similar to other reports
Discussion
The etiology of renal cancer is highly complex and involves both environmental and genetic factors. Chronic inflammation appears to make an essential contribution [28]. In addition, genetic polymorphisms in cytokine genes can influence the expression or function of these cytokines, and polymorphisms in genes that regulate the intensity of immune responses may contribute to the pathogenesis of renal cancer and influence the clinical outcome of patients [6], [29]. This study analyzed genetic
Acknowledgments
We thank Ms. Eva García and Ms. Ana Isabel Rodríguez for technical assistance. This study was supported by grants from the Fondo de Investigaciones Sanitarias (FIS), Red Genomica del Cancer (RETIC RD 06/0020), Plan Andaluz de Investigacion (Group CTS 143), Consejeria Andaluz de Salud (SAS), Proyecto de Excelencia de Consejeria de Innovacion (CTS 695), Proyecto de investigacion I+D (SAF 2007-63262) in Spain; and from the Integrated European Cancer Immunotherapy project (OJ2004/C158, 518234).
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Cited by (26)
Interleukin 18: Friend or foe in cancer
2013, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Thus, the expression of IL-18 by tumor cells in human skin tissue may provide an important clue to the understanding of pathogenesis of malignant skin tumors [37]. High levels of IL-18 production may play a major role in the growth and metastasis of renal cancer [38]. Higher expression of IL-18 is detected in various cancer cells [39].
Alleles and genotypes of polymorphisms of IL-18, TNF-α and IFN-γ are associated with a higher risk and severity of hepatocellular carcinoma (HCC) in Brazil
2013, Human ImmunologyCitation Excerpt :Saenz-Lopez et al. investigated whether the presence of SNPs -137G/C and -607C/A of IL-18 were associated with size, grade, and TNM Classification of 158 patients with renal cell carcinoma. These authors observed that genotype -607CC was significantly associated with larger tumor size (P = 0.001), grade (P = 0.030), and T (P = 0.001) and M (P = 0.012) stage, while genotype -137GG was correlated with larger tumor size (P = 0.036), grade (P = 0.017), and stage T (P = 0.026) [23]. Another authors, studing the association of SNPs -607C/A and -137G/C of IL-18 with histology of colorectal and gastric cancer (moderately differentiated or undifferentiated vs. well differentiated), noticed that no difference in genotype frequency was detected, although the combination of genotypes -607AA/-137GC was more frequent among patients with less differentiated tumors [24].
Genetic variants in interleukin-18 gene and risk for cervical squamous cell carcinoma
2013, Human ImmunologyCitation Excerpt :The +105 A/C polymorphism in exon 4 is found to affect IL-18 production by purified peripheral blood monocytes [20]. These functional SNPs have been investigated in various kinds of cancer susceptibility [21–29]. Further details of IL-18 SNPs on gene/protein functions and risk to different cancers can be found in Table 1.
Association of IL-12, IL-18 variants and serum IL-18 with bladder cancer susceptibility in North Indian population
2013, GeneCitation Excerpt :Variant C allele of IL18 (− 137) G/C was also associated with 1.6 fold risk for BC. However there were studies showing no association in case of renal cell carcinoma (Sáenz-López et al., 2010), nasopharyngeal carcinoma (Farhat et al., 2008), head & neck carcinoma (Asefi et al., 2009) and recurrent spontaneous abortion (Naeimi et al., 2006). We observed risk of 1.5 folds in IL18 (− 607) C/A, heterozygote genotype that was compatible with (Nikiteas et al., 2007) study showing 3 fold risk in colorectal cancer and 2.6 fold risk in lung cancer in heterozygous CA genotype by Farjadfar et al., 2009.
Association between C13ORF31, NOD2, RIPK2 and TLR10 polymorphisms and urothelial bladder cancer
2012, Human ImmunologyCitation Excerpt :The genotyping of the polymorphisms was performed using predesigned TaqMan SNP Genotyping Assays (Applied Biosystems, Foster City, CA). Amplification assays and reaction conditions were described previously [11]. The following single-nucleotide polymorphisms were typed: NOD2 A/G rs9302752, RIPK2 A/T rs42490, C13ORF31 C/T rs3764147 and TLR10 C/T rs4129009 and T/G rs11096955.
Contribution of inflammatory cytokine interleukin-18 genotypes to renal cell carcinoma
2019, International Journal of Molecular Sciences
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The authors Pablo Sáenz-López and Rafael Carretero have equally contributed to this work and the two should be considered as first authors.
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The José Manuel Cózar and Francisco Ruiz-Cabello authors have equally contributed to this work and the two should be considered as last authors.