RAP1 GTPase overexpression is associated with cervical intraepithelial neoplasia

PLoS One. 2015 Apr 9;10(4):e0123531. doi: 10.1371/journal.pone.0123531. eCollection 2015.

Abstract

RAP1 (RAS proximate 1), a small GTP-binding protein of the RAS superfamily, is a putative oncogene that is highly expressed in several malignant cell lines and types of cancers, including some types of squamous cell carcinoma. However, the participation of RAP1 in cervical carcinogenesis is unknown. We conducted a cross-sectional study of paraffin-embedded cervical biopsies to determine the association of RAP1 with cervical intraepithelial neoplasia (CIN). Standard and quantitative immunohistochemistry assessment of RAP1 expression in fixed tissue was performed on 183 paraffin-embedded cervical biopsies that were classified as normal or non-dysplastic mucosa (NDM) (n = 33); CIN grade 1 (n = 84) and CIN grade 2/3 (n = 66). A gradual increase in RAP1 expression in NDM < CIN 1 < CIN 2/3 (p<0.001) specimens was observed and was in agreement with the histopathologic diagnosis. A progressive increase in the RAP1 expression levels increased the risk of CIN 1 [odds ratio (OR) = 3.50; 95% confidence interval (CI) 1.30-10.64] 3.5 fold and the risk of CIN 2/3 (OR = 19.86, 95% CI 6.40-70.79) nearly 20 fold when compared to NDM. In addition, stereotype ordinal regression analysis showed that this progressive increase in RAP1 expression more strongly impacted CIN 2/3 than CIN 1. Our findings suggest that RAP1 may be a useful biomarker for the diagnosis of CIN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers, Tumor / biosynthesis*
  • Biomarkers, Tumor / genetics
  • Carcinogenesis / genetics
  • Carcinoma, Squamous Cell / diagnosis
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Middle Aged
  • Neoplasm Staging
  • Risk Factors
  • Shelterin Complex
  • Telomere-Binding Proteins / biosynthesis*
  • Telomere-Binding Proteins / genetics
  • Uterine Cervical Dysplasia / diagnosis
  • Uterine Cervical Dysplasia / genetics*
  • Uterine Cervical Dysplasia / pathology

Substances

  • Biomarkers, Tumor
  • Shelterin Complex
  • TERF2IP protein, human
  • Telomere-Binding Proteins

Grants and funding

This research was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-www.cnpq.br), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES — www.capes.gov.br), and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG - www.fapemig.br). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.