TNFR1 single nucleotide polymorphisms are not associated with cervical HPV-induced pre-malignant lesion but regulate in situ cervical TNFR1 expression

Natália Pereira da Rocha; Elyzabeth Avvad-Portari; Fábio Russomano; Eric Henrique Roma; Amanda Chaves Pinto; Evandro Klumb; Jacyara Macedo; Ana Teresa Gomes Fernandes; Maria da Glória Bonecini-Almeida

doi:10.18632/oncotarget.26627

TNFR1 single nucleotide polymorphisms are not associated with cervical HPV-induced pre-malignant lesion but regulate in situ cervical TNFR1 expression

Oncotarget. 2019 Jan 29;10(9):953-965. doi: 10.18632/oncotarget.26627.

Authors

Natália Pereira da Rocha¹, Elyzabeth Avvad-Portari², Fábio Russomano³, Eric Henrique Roma¹, Amanda Chaves Pinto⁴, Evandro Klumb⁵, Jacyara Macedo⁴, Ana Teresa Gomes Fernandes¹, Maria da Glória Bonecini-Almeida¹

Affiliations

¹ Laboratory of Immunology and Immunogenetics in Infectious Diseases, Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
² Department of Pathologic Anatomy, Fernandes Figueira Woman, Child and Adolescent National Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
³ Women's Health Care Area, Fernandes Figueira Woman, Child and Adolescent National Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
⁴ Department of Biochemistry, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
⁵ Department of Rheumatology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

Abstract

TNF-α is involved in HPV infection control by triggering cell signaling through binding in specific receptors TNFR1 and TNFR2. Genetic polymorphisms in these receptors may influence TNF-α signaling. Herein, we investigated TNFR1 rs767455 and rs2234649 single nucleotide polymorphisms, and TNFR1 protein expression in cervical squamous intraepithelial lesions (SIL) to identify their role in cervical pre-malignant development. SIL patients (n = 179) and healthy volunteers (n = 227) were enrolled for TNFR1 genotyping analysis by PCR-RFLP in blood samples and TNFR1 protein expression in cervical tissue by immunohistochemistry. No statistical differences regard genotypes and allelic frequencies for both polymorphisms were observed. Cervical TNFR1-expressing cells were rare in epithelium and basal layer regardless the groups. However, a progressive increase in infiltrating cells was observed in the stromal area, mainly in high SIL (HSIL) group compared to low SIL (LSIL, p < 0.001) and control (p < 0.001) groups. TNFR1-expressing cells frequency was higher in TNFR1 rs767455AG/GG (p < 0.001), and in rs2234649AA (p < 0.001) genotypes carries in HSIL subgroup. These data indicated that TNFR1-expression is abrogated in cervical epithelium, where HPV-induced pre-malignant lesion occurs, increasing its frequency in inflammatory cells in stroma, and is genetically controlled by TNFR1 rs767455AG/GG and rs234649AA genotypes. These biomarkers may be useful to identify cervical precancerous lesions progression.

Keywords: HPV; TNFR1 SNPs; cervical lesions; in situ TNFR1.