Distinct and Competitive Regulatory Patterns of Tumor Suppressor Genes and Oncogenes in Ovarian Cancer

Min Zhao,Zhongming Zhao,Jingchun Sun,Szabolcs Semsey

doi:10.1371/journal.pone.0044175

Abstract

BackgroundSo far, investigators have found numerous tumor suppressor genes (TSGs) and oncogenes (OCGs) that control cell proliferation and apoptosis during cancer development. Furthermore, TSGs and OCGs may act as modulators of transcription factors (TFs) to influence gene regulation. A comprehensive investigation of TSGs, OCGs, TFs, and their joint target genes at the network level may provide a deeper understanding of the post-translational modulation of TSGs and OCGs to TF gene regulation.Methodology/Principal FindingsIn this study, we developed a novel computational framework for identifying target genes of TSGs and OCGs using TFs as bridges through the integration of protein-protein interactions and gene expression data. We applied this pipeline to ovarian cancer and constructed a three-layer regulatory network. In the network, the top layer was comprised of modulators (TSGs and OCGs), the middle layer included TFs, and the bottom layer contained target genes. Based on regulatory relationships in the network, we compiled TSG and OCG profiles and performed clustering analyses. Interestingly, we found TSGs and OCGs formed two distinct branches. The genes in the TSG branch were significantly enriched in DNA damage and repair, regulating macromolecule metabolism, cell cycle and apoptosis, while the genes in the OCG branch were significantly enriched in the ErbB signaling pathway. Remarkably, their specific targets showed a reversed functional enrichment in terms of apoptosis and the ErbB signaling pathway: the target genes regulated by OCGs only were enriched in anti-apoptosis and the target genes regulated by TSGs only were enriched in the ErbB signaling pathway.Conclusions/SignificanceThis study provides the first comprehensive investigation of the interplay of TSGs and OCGs in a regulatory network modulated by TFs. Our application in ovarian cancer revealed distinct regulatory patterns of TSGs and OCGs, suggesting a competitive regulatory mechanism acting upon apoptosis and the ErbB signaling pathway through their specific target genes.

Highlights

Cancer is characterized by uncontrolled cell growth, which is caused by the accumulated genomic mutations in genes that normally play important roles in controlling cell proliferation and apoptosis [1]
We extracted a subnetwork centered with these known tumor suppressor genes (TSGs), OCGs, transcription factors (TFs), and their direct interactors from the human protein-protein interactions (PPIs) network
The output of MINDy was a regulatory network that comprised the top layer with modulators (TSGs and OCGs), the middle layer with TFs, and the bottom layer with joint target genes of the two top layers

Summary

Introduction

Cancer is characterized by uncontrolled cell growth, which is caused by the accumulated genomic mutations in genes that normally play important roles in controlling cell proliferation and apoptosis [1]. The second group of genes are oncogenes, whose gain of function can trigger cancer development [3]. Hereafter, we abbreviated these two types of genes as TSGs and OCGs. Many TSGs are the ‘‘guardian of the cell’’ because of their critical roles in cell cycle checkpoints and inducing apoptosis [2,4]. Investigators have found numerous tumor suppressor genes (TSGs) and oncogenes (OCGs) that control cell proliferation and apoptosis during cancer development. A comprehensive investigation of TSGs, OCGs, TFs, and their joint target genes at the network level may provide a deeper understanding of the post-translational modulation of TSGs and OCGs to TF gene regulation

Methods

Results

Conclusion