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Influence of functional polymorphisms in TNF-α, IL-8, and IL-10 cytokine genes on mRNA expression levels and risk of gastric cancer

  • Research Article
  • Published:
Tumor Biology

Abstract

Functional polymorphisms in promoter regions can produce changes in the affinity of transcription factors, thus altering the messenger ribonucleic acid (mRNA) expression levels of inflammatory cytokines associated with the risk of cancer development. The goal of this study was to evaluate the influence that polymorphisms in the cytokine genes known as TNF-α-308 G/A (rs1800629), TNF-α-857 C/T (rs1799724), IL-8-251 T/A (rs4073), IL-8-845 T/C (rs2227532), and IL-10-592 C/A (rs1800872) have on changes to mRNA expression levels and on the risks of chronic gastritis (CG) and gastric cancer (GC). A sample of 723 individuals was genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Relative mRNA expression levels were measured using quantitative real-time PCR (qPCR). Polymorphisms TNF-α-308 G/A and IL-8-251 A/T were not associated with risks of these gastric lesions. However, TNF-α-857 C/T, IL-8-845 T/C, and IL-10-592 C/A were found to be associated with a higher risk of GC, and IL-10-592 C/A was found to be associated with a higher risk of CG. The relative mRNA expression levels (RQ) of TNF-α, IL-8, and IL-10 were markedly downregulated in the CG group (median RQs = 0.128, 0.247, and 0.614, respectively), while the RQ levels of TNF-α in the GC group were upregulated (RQ = 2.749), but were basal for IL-8 (RQ = 1.053) and downregulated for IL-10 (RQ = 0.179). When the groups were stratified according to wild-type and polymorphic alleles, only for IL-8-845 T/C the polymorphic allele was found to influence the expression levels of this cytokine. IL-8-845 C allele carriers were significantly upregulated in both groups (GC and CG; RQ = 3.138 and 2.181, respectively) when compared to TT homozygotes (RQ = −0.407 and 0.165, respectively). In silico analysis in the IL-8 promoter region revealed that the presence of the variant C allele in position -845 is responsible for the presence of the binding sites for two transcription factors (REL and CREB1), which are involved in increased gene expression. Polymorphic alleles were not shown to have any effect on the expression levels of TNF-α and IL-10. Taken together, our findings provide evidence for an association of TNF-α-857 C/T, IL-8-845 T/C, and IL-10-592 C/A with a higher risk of gastric cancer and also demonstrate the influence that the polymorphic C allele of IL-8-845 has on changes to the gene expression levels of this cytokine.

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Abbreviations

C:

Control

CG:

Chronic gastritis

cDNA:

Complementary deoxyribonucleic acid

CI:

Confidence interval

EDTA:

Ethylenediaminetetraacetic acid

GC:

Gastric cancer

IL:

Interleukin

IL-8:

Interleukin-8

IL-10:

Interleukin-10

LPS:

Lipopolysaccharide

mRNA:

Messenger ribonucleic acid

OR:

Odds ratio

PCR:

Polymerase chain reaction

RFLP:

Restriction fragment length polymorphism

RQ:

Relative quantification

SNP:

Single-nucleotide polymorphism

TNF-α:

Tumor necrosis factor alpha

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Acknowledgments

The authors are grateful to Joice Matos Biselli-Périco for help with the gene expression figures and also to José Antonio Cordeiro for support with the statistical analysis. This study was partially funded by the São Paulo Research Foundation (FAPESP), No. 2010/00507-0, and also by the Brazilian National Council for Scientific and Technological Development (CNPq), No. 471908/2010-0.

Conflicts of interest

None

Authors’ contributions

AES and JGO conceived and designed the experiments. JGO, AFT, DMN, and ACTC performed the experiments. JGO, AES, and ACTC analyzed and interpreted the data. YCJ, MCV, PR, EMGB, ECP, and AES contributed the set of samples, reagents, materials, and analysis tools. JGO and AES drafted the manuscript and revised it carefully. All authors have approved the final version of manuscript to be published.

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Authors and Affiliations

  1. Cytogenetics and Molecular Biology Laboratory, Department of Biology, Sao Paulo State University (UNESP), Rua Cristovão Colombo, 2265, São José do Rio Preto, 15054-000, SP, Brazil

    Juliana Garcia de Oliveira, Ana Flávia Teixeira Rossi, Aline Cristina Targa Cadamuro, Yvana Cristina Jorge & Ana Elizabete Silva

  2. Department of Graduate Studies and Research, Sacred Heart University (USC), Rua Irmã Arminda, 10-50, Bauru, 17011-970, SP, Brazil

    Juliana Garcia de Oliveira

  3. Department of Genetics and Molecular Biology, São José do Rio Preto School of Medicine (FAMERP), Av. Brigadeiro Faria Lima, 5416, São José do Rio Preto, 15090-000, SP, Brazil

    Daniela Manchini Nizato, Érika Cristina Pavarino & Eny Maria Goloni-Bertollo

  4. Genomics Laboratory, Department of Biology, Sao Paulo State University (UNESP), Rua Cristovão Colombo, 2265, São José do Rio Preto, 15054-000, SP, Brazil

    Marina Curado Valsechi & Paula Rahal

  5. Laboratory for the Study of Hemoglobin and the Genetics of Hematologic Diseases, Department of Biology, Sao Paulo State University (UNESP), Rua Cristovão Colombo, 2265, São José do Rio Preto, 15054-000, SP, Brazil

    Larissa Paola Rodrigues Venâncio

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  1. Juliana Garcia de Oliveira
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de Oliveira, J.G., Rossi, A.F.T., Nizato, D.M. et al. Influence of functional polymorphisms in TNF-α, IL-8, and IL-10 cytokine genes on mRNA expression levels and risk of gastric cancer. Tumor Biol. 36, 9159–9170 (2015). https://doi.org/10.1007/s13277-015-3593-x

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