TOP2A and CENPF are synergistic master regulators activated in cervical cancer

Abstract

Background Identification of master regulators (MRs) using transcriptome data in cervical cancer (CC) could help us to develop biomarkers and find novel drug targets to fight this disease. Methods We performed differential expression (DE) analyses of public microarray and RNA-seq transcriptome data of CC and normal cervical tissues (N). Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER) was used to convert the DE outcomes to differential activity (DA) signature for MRs. Synergy analysis was conducted to study synergistic effect of MR-pairs. TCGA and microarray data were used to test the association of expression of a MR and a clinical feature or a molecular feature (e.g. somatic mutations). Various bioinformatic tools/websites (DAVID, GEPIA2, Oncomine, cBioPortal) were used to analyze the expression of the top MRs and their regulons. Results Ten DE and 10 DA signatures were generated for CC. Two MRs, DNA topoisomerase II alpha (TOP2A) and centromere protein F (CENPF) were found to be up-regulated, activated and synergistic in CC compared to N across the 10 datasets. The two MRs activate a common set of genes (regulons) with functions in cell cycle, chromosome, DNA damage etc. Higher expression of CENPF was associated with metastasis. High expression of both MRs is associated with somatic mutation of a set of genes including tumor suppressors (TP53, MSH2, RB1) and genes involved in cancer pathways, cell cycle, DNA damage and repair. The magnitude of up-regulation and the absolute expression level of both MRs in CC are significantly higher compared to many other cancer types. Conclusion TOP2A and CENPF are a synergistic pair of MRs that are overexpressed and activated in CC. Their high expression is correlated with some prognosis features (e.g. metastasis) and molecular features (e.g. somatic mutations) and distinctly high in CC vs. many other cancer types. They may be good biomarkers and anticancer drug targets for CC.

SARS-CoV-2 potential drugs, drug targets, and biomarkers: a viral-host interaction network-based analysis

“…Further studies are needed to investigate the effect of targeting CENPF and CIT as a possible therapeutic strategy to treat COVID-19. It is worth mentioning that the overexpression of CENPF and CIT, as is the case in this study, has been associated with different types of cancer such as cervical cancer, hepatocellular carcinoma, osteosarcoma, bladder cancer, and esophageal squamous cell carcinoma [49][50][51][52][53] . Targeting MYB may be also an alternative strategy to inhibit CENPF and indirectly control viral replication.…”

Bioinformatics analysis of differentially expressed genes and pathways in the development of cervical cancer

“…We can track the influence of some key regulatory genes in cervical cancer through related research. For example, Beiwei Yu et al [ 64 ] showed that TOP2A and CENPF are synergic master regulators that are activated in cancer. Jinhui Liu et al [ 33 ] showed that RMI2 was a novel key gene in CESC.…”

Network-based Inference of Hub Genes in Epithelial Membrane Protein 2-treated Human RPE cells

“…The Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER) [10][11][12] algorithm has proven to be a useful tool for estimating regulator activity from gene expression data using enriched regulon analysis. VIPER R package was used to compare APs in each group.…”