γH2Ax Expression as a Potential Biomarker Differentiating between Low and High Grade Cervical Squamous Intraepithelial Lesions (SIL) and High Risk HPV Related SIL.

Konstantinos Leventakos,Asimakis Pappas,Petros Karakitsos,Christine Kottaridi,Maria Kefala,Alina-Roxani Gouloumi,Aris Spathis,Sotirios Tsiodras,Ioannis Panayiotides,Theodore Kelesidis,Abraham Pouliakis,Vasileios Sioulas,Charalambos Chrelias

doi:10.1371/journal.pone.0170626

Konstantinos Leventakos, Asimakis Pappas + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0170626

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Journal: PloS one	Publication Date: Jan 24, 2017
Citations: 1	License type: CC BY 4.0

Affiliation: National and Kapodistrian University of Athens

Abstract

BackgroundγH2AX is a protein biomarker for double-stranded DNA breakage; its expression was studied in cervical squamous intraepithelial lesions and carcinomas.MethodsImmunostaining for phospho-γH2AX was performed in sections from histologically confirmed cervical SIL and carcinomas, as well as from normal cervices used as controls. In total, 275 cases were included in the study: 112 low grade SIL (LGSIL), 99 high grade SIL (HGSIL), 24 squamous cell carcinoma (SCC), 12 adenocarcinoma and 28 cervical specimens with no essential lesions. Correlation of histological grading, high risk vs. low risk HPV virus presence, activated vs. non-activated status (by high risk HPV mRNA expression) and γH2AX expression in both basal and surface segments of the squamous epithelium was performed.ResultsGradual increase of both basal and surface γH2AX expression was noted up from normal cervices to LGSIL harboring a low risk HPV type, to LGSIL harboring a high risk virus at a non-activated state (p<0.05). Thereafter, both basal and surface γH2AX expression dropped in LGSIL harboring a high risk virus at an activated state and in HGSIL.ConclusionsγH2AX could serve as a potential biomarker discriminating between LGSIL and HGSIL, as well as between LGSIL harboring high risk HPV at an activated state.

Highlights

Infection by HPV is responsible for the development of cervical squamous intraepithelial lesions (SIL) and cervical carcinoma, as well as for other squamous cell carcinomas in the anogenital and the head and neck area
Gradual increase of both basal and surface γH2AX expression was noted up from normal cervices to LGSIL harboring a low risk HPV type, to LGSIL harboring a high risk virus at a non-activated state (p
Conclusions γH2AX could serve as a potential biomarker discriminating between LGSIL and HGSIL, as well as between LGSIL harboring high risk HPV at an activated state

Summary

Introduction

Infection by HPV is responsible for the development of cervical squamous intraepithelial lesions (SIL) and cervical carcinoma, as well as for other squamous cell carcinomas in the anogenital and the head and neck area. Dysregulation of the DNA damage response (DDR) mechanism has been implicated in the pathogenesis of a multitude of malignancies and is currently investigated, in order to identify predictors of disease progression as well as novel therapeutic targets [1]. Genomic instability is important in the pathogenesis of cervical cancer and it is driven by the integration of DNA from high risk HPV types [1]. Genomic instability has been associated with the formation of DNA double-strand breaks (DSBs) [1]; the DDR pathway exerts anti-tumor action by inducing p53-dependent cell cycle arrest, apoptosis and senescence [1]. ΓH2AX is a protein biomarker for double-stranded DNA breakage; its expression was studied in cervical squamous intraepithelial lesions and carcinomas

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Conclusion