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Tumor Biology

, Volume 36, Issue 12, pp 9159–9170 | Cite as

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

  • Juliana Garcia de Oliveira
  • Ana Flávia Teixeira Rossi
  • Daniela Manchini Nizato
  • Aline Cristina Targa Cadamuro
  • Yvana Cristina Jorge
  • Marina Curado Valsechi
  • Larissa Paola Rodrigues Venâncio
  • Paula Rahal
  • Érika Cristina Pavarino
  • Eny Maria Goloni-Bertollo
  • Ana Elizabete Silva
Research Article

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.

Keywords

Cytokines Gastric cancer Chronic gastritis Gene polymorphisms Gene expression 

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

Notes

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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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Juliana Garcia de Oliveira
    • 1
    • 2
  • Ana Flávia Teixeira Rossi
    • 1
  • Daniela Manchini Nizato
    • 3
  • Aline Cristina Targa Cadamuro
    • 1
  • Yvana Cristina Jorge
    • 1
  • Marina Curado Valsechi
    • 4
  • Larissa Paola Rodrigues Venâncio
    • 5
  • Paula Rahal
    • 4
  • Érika Cristina Pavarino
    • 3
  • Eny Maria Goloni-Bertollo
    • 3
  • Ana Elizabete Silva
    • 1
  1. 1.Cytogenetics and Molecular Biology Laboratory, Department of BiologySao Paulo State University (UNESP)São José do Rio PretoBrazil
  2. 2.Department of Graduate Studies and ResearchSacred Heart University (USC)BauruBrazil
  3. 3.Department of Genetics and Molecular BiologySão José do Rio Preto School of Medicine (FAMERP)São José do Rio PretoBrazil
  4. 4.Genomics Laboratory, Department of BiologySao Paulo State University (UNESP)São José do Rio PretoBrazil
  5. 5.Laboratory for the Study of Hemoglobin and the Genetics of Hematologic Diseases, Department of BiologySao Paulo State University (UNESP)São José do Rio PretoBrazil

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