Article

Polymorphisms in the IL-13 and IL-4R genes are associated with the development of renal cell carcinoma

State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Department of Molecular & Genetic Toxicology, School of Public Health, Nanjing Medical University, and Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Annals of Oncology (Impact Factor: 7.04). 02/2012; 23(8):2114-21. DOI: 10.1093/annonc/mdr607
Source: PubMed

ABSTRACT

Cytokines are the important modulators that bind to their relevant receptors in response to some stimuli to mediate the homeostasis. It has been suggested that the imbalance of immune system of the host might affect the generation of diseases, including cancers.
We investigated the association between six functional polymorphisms of IL-4, IL-13, and IL-4R genes and susceptibility to renal cell cancer in a hospital-based study, including 620 renal cell carcinoma (RCC) patients and 623 controls. Logistic regression model was used to assess the genetic effects on the development of RCC.
Overall, individuals with IL-4R Ile50Val CT/TT genotypes had a 0.34-fold significantly decreased RCC risk (CT/TT versus CC), and the T variant allele was associated with a decreased risk of RCC in a dose-response manner (Ptrend=0.009). In addition, we also observed that IL-13 C-1055T and Arg130Gln polymorphisms could decrease the risk of RCC [TT versus CC/CT: odds ratio=0.36, 95% confidence interval (CI)=0.16-0.78; AA versus GG/GA: 0.66, 0.44-0.97, respectively]. Furthermore, a multiplicative interaction association between the combined IL-4R Ile50Val and IL-13 C-1055T genotypes was observed to decrease the risk of RCC (P=0.036).
IL-13 and IL-4R may play an important role in the etiology of RCC.

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    • "IL-13 binds to two receptor subunits, IL-13 receptor subunit alpha-1 (IL13Rα1) and IL-13 receptor subunit alpha-2 (IL13Rα2). IL13Rα2 has been shown to be highly expressed in many tumor types, such as colon, glioblastoma, ovarian, head and neck, kidney, and mesothelioma, but not by most normal cells such as immune cells or endothelial cells456789. IL13Rα2 is also associated with poor prognosis in human cancers and a target for cancer therapy1011. "
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    ABSTRACT: IL-13 receptor subunit alpha-2 (IL13Rα2) is associated with poor prognosis in some cancers. However, the role of IL13Rα2 in lung cancer remains unknown. We showed that IL13Rα2 overexpression was associated with late stages of disease progression and shorter disease-free survival (DFS) as well as overall survival (OS) in resected lung cancer patients. IL13Rα2 promoted the migration, invasion and anoikis resistance of lung cancer cells in vitro. Silencing of IL13Rα2 in lung cancer cells decreased invasion in vitro and lung metastasis in vivo. IL13Rα2 activated phosphatidylinositol 3 kinase (PI3K), Akt, and transcriptional coactivator with PDZ-binding motif (TAZ). Inhibition of PI3K attenuated activation of TAZ and its downstream target genes by IL13Rα2. We suggest that inhibition of IL13Rα2 is a potential therapeutic approach in lung cancer.
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    ABSTRACT: The results from the published studies on the relationship between GSTM1/GSTT1 null genotypes and renal cell carcinoma (RCC) risk are still conflicting. This meta-analysis was performed to evaluate the relationship between GSTM1/GSTT1 null genotypes and RCC susceptibility. Association studies were identified from the databases of PubMed, Embase, Cochrane Library, and CBM-disc (China Biological Medicine Database) on 1 February 2012, and eligible investigations from 1950 to 2012 were synthesized using meta-analysis method. Results were expressed as odds ratios (ORs) for dichotomous data, and 95% confidence intervals (CIs) were also calculated. Six studies were identified for the analysis of association between polymorphic deletion of GSTM1/GSTT1 and RCC risk. There was no association between GSTM1/GSTT1 null genotype and RCC susceptibility (GSTM1: N = 6, p-heterogeneity = 0.07, OR = 1.07, 95% CI: 0.85-1.35, p = 0.57; GSTT1: N = 6, p-heterogeneity < 0.00001, OR = 0.98, 95% CI: 0.58-1.65, p = 0.94). Interestingly, null genotype of GSTT1 was associated with RCC risk in Caucasians and Asians (Caucasians: N = 4, p-heterogeneity = 0.38, OR = 0.76, 95% CI: 0.61-0.95, p = 0.01; Asians: N = 1, OR = 2.39, 95% CI: 1.63-3.51, p < 0.00001). For the GSTM1-GSTT1 interaction analysis, the dual null genotype of GSTM1/GSTT1 was not significantly associated with RCC susceptibility (N = 4, p-heterogeneity = 0.006, OR = 1.17, 95% CI: 0.98-1.39, p = 0.09). However, the dual null genotype of GSTM1-GSTT1 was associated with RCC risk in Asians (N = 1, OR = 2.06, 95% CI: 1.36-3.13, p = 0.007). In conclusion, our study results suggest that GSTT1 null genotype is associated with the RCC susceptibility in Caucasians and Asians, and the dual null genotype of GSTM1-GSTT1 is associated with RCC risk in Asians. However, more genetic epidemiological investigations are required to further explore this relationship.
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    ABSTRACT: Background/aims: Interleukin-13 (IL13) is an immunoregulatory cytokine which plays an important role in carcinogenesis through affecting tumor immunosurveillance. Many studies had reported the influence of IL13 rs1800925 and rs20541 polymorphisms on cancer risk, however, with inconclusive results. The aim of the present study was to conduct a meta-analysis to clarify the relationship. Methods: Twenty studies including a total of 6713 cancer cases and 8693 controls for IL13 rs20541 polymorphism and 4081 cancer cases and 6202 controls for IL13 rs1800925 polymorphism were included in the meta-analysis. Data were extracted from these studies and odds ratios with corresponding 95% confidence intervals were computed to estimate the strength of the association. Results: Overall, the IL13 rs20541 polymorphism were associated with significantly decreased cancer risk in all genetic models (AA vs. GG: OR=0.82, 95%CI=0.71-0.95; GA vs. GG: OR=0.92, 95%CI=0.85-0.99; GA/AA vs. GG: OR=0.90, 95%CI=0.85-0.97; AA vs. GG/GA: OR=0.85, 95CI%=0.74-0.98). In the stratified analyses, significant effects were found among European populations, studies with population-based controls and studies of glioma. No influence of the IL13 rs1800925 polymorphism on the overall cancer risk was observed. However, in the stratified analyses, we found the IL13 rs1800925 polymorphism was significantly associated with decreased risk for glioma (CT vs. TT: OR=0.72, 95%CI=0.55-0.93; CT/TT vs. TT: OR=0.76, 95%CI=0.62-0.89). Conclusion: Our meta-analysis suggests that the IL13 rs20541 polymorphism contributes to susceptibility to cancer, especially for glioma; and the IL13 rs1800925 polymorphism may be associated with glioma risk.
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