Potential biomarkers and therapeutic targets in cervical cancer: Insights from the meta-analysis of transcriptomics data within network biomedicine perspective.

Medi Kori,Kazim Yalcin Arga,Craig Meyers

doi:10.1371/journal.pone.0200717

Abstract

The malignant neoplasm of the cervix, cervical cancer, has effects on the reproductive tract. Although infection with oncogenic human papillomavirus is essential for cervical cancer development, it alone is insufficient to explain the development of cervical cancer. Therefore, other risk factors such as host genetic factors should be identified, and their importance in cervical cancer induction should be determined. Although gene expression profiling studies in the last decade have made significant molecular findings about cervical cancer, adequate screening and effective treatment strategies have yet to be achieved. In the current study, meta-analysis was performed on cervical cancer-associated transcriptome data and reporter biomolecules were identified at RNA (mRNA, miRNA), protein (receptor, transcription factor, etc.), and metabolite levels by the integration of gene expression profiles with genome-scale biomolecular networks. This approach revealed already-known biomarkers, tumor suppressors and oncogenes in cervical cancer as well as various receptors (e.g. ephrin receptors EPHA4, EPHA5, and EPHB2; endothelin receptors EDNRA and EDNRB; nuclear receptors NCOA3, NR2C1, and NR2C2), miRNAs (e.g., miR-192-5p, miR-193b-3p, and miR-215-5p), transcription factors (particularly E2F4, ETS1, and CUTL1), other proteins (e.g., KAT2B, PARP1, CDK1, GSK3B, WNK1, and CRYAB), and metabolites (particularly, arachidonic acids) as novel biomarker candidates and potential therapeutic targets. The differential expression profiles of all reporter biomolecules were cross-validated in independent RNA-Seq and miRNA-Seq datasets, and the prognostic power of several reporter biomolecules, including KAT2B, PCNA, CD86, miR-192-5p and miR-215-5p was also demonstrated. In this study, we reported valuable data for further experimental and clinical efforts, because the proposed biomolecules have significant potential as systems biomarkers for screening or therapeutic purposes in cervical carcinoma.

Highlights

Cervical cancer is a malignant neoplasm originating from cells derived from cervix squamocolumner junction of the uterine cervix
The individual statistical analyses of five gene expression datasets resulted in the identification of hundreds of up- and down-regulated differentially expressed genes (DEGs) (Fig 1A and 1B) and revealed the reprogramming of 3%-10% of the genome in cervical cancer
Considering that oncogenic Human Papillomavirus (HPV) infection is necessary but not sufficient for the development of cervical cancer, the elucidation of the molecular mechanisms that occur as a consequence of the genetic and environmental factors playing a role in the pathogenesis of this disease is a great challenge

Summary

Introduction

Cervical cancer is a malignant neoplasm originating from cells derived from cervix squamocolumner junction of the uterine cervix. The computational integration of biomolecular networks with data from different omic levels represents the core of research in the field of systems biology This interdisciplinary field provides valuable information on genome reprogramming under disease conditions and relevant biological entities that might be considered potential diagnostic or therapeutic targets [8]. Survival analyses were performed and the prognostic power of selected reporter biomolecules was identified via crossvalidation using independent gene expression datasets This systematic study reports candidate biomolecules that can be considered as diagnostic/prognostic biomarkers or potential therapeutic targets for further experimental and clinical trials for cervical cancer

Materials and methods

Results

Discussion