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.
Highlights
Cervical cancer, which is caused by high-risk Human papillomavirus (HR-HPV), is the second most frequent cancer in women worldwide [1]
The RAP1 and p16INK4A expression levels in non-dysplastic mucosa (NDM), cervical intraepithelial neoplasia (CIN) 1, and CIN 2/3 lesions are shown in Fig 2, in S1 Fig and Table 1, which include the HPV-16, HPV-18 and HPV-31 types that were detected in the CIN groups. p16INK4A was used as an immunohistochemical reference for our study
Unlike what was observed in NDM, RAP1 expression was observed in 100% of the CIN 1 samples
Summary
Cervical cancer, which is caused by high-risk Human papillomavirus (HR-HPV), is the second most frequent cancer in women worldwide [1]. In HPV-infected epithelial cells, the interaction of the HPV E2 protein with the cellular bromodomain protein Brd, a cell cycle progression regulator, enhances the RAP GAP activity of SPA-1, which disrupts the proper balance of RAP1 activation [21]. Those findings led us to investigate the expression levels of RAP1 in low- and high-grade CIN lesions to address the potential use of this putative oncogene as a cervical neoplasia biomarker. We found a strong association of RAP1 overexpression in high grade lesions
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