Abstract
BackgroundEstrogen receptors (ERs) are thought to play an important role in non-small cell lung cancer (NSCLC). However, the effect of ERs in NSCLC is still controversial and needs further investigation. A new consideration is that ERs may affect NSCLC progression through complicated molecular signaling networks rather than individual targets. Therefore, this study aims to explore the effect of ERs in NSCLC from the perspective of cancer systems biology.MethodsThe gene expression profile of NSCLC samples in TCGA dataset was analyzed by bioinformatics method. Variations of cell behaviors and protein expression were detected in vitro. The kinetic process of molecular signaling network was illustrated by a systemic computational model. At last, immunohistochemical (IHC) and survival analysis was applied to evaluate the clinical relevance and prognostic effect of key receptors in NSCLC.ResultsBioinformatics analysis revealed that ERs might affect many cancer-related molecular events and pathways in NSCLC, particularly membrane receptor activation and signal transduction, which might ultimately lead to changes in cell behaviors. Experimental results confirmed that ERs could regulate cell behaviors including cell proliferation, apoptosis, invasion and migration; ERs also regulated the expression or activation of key members in membrane receptor signaling pathways such as epidermal growth factor receptor (EGFR), Notch1 and Glycogen synthase kinase-3β/β-Catenin (GSK3β/β-Catenin) pathways. Modeling results illustrated that the promotive effect of ERs in NSCLC was implemented by modulating the signaling network composed of EGFR, Notch1 and GSK3β/β-Catenin pathways; ERs maintained and enhanced the output of oncogenic signals by adding redundant and positive-feedback paths into the network. IHC results echoed that high expression of ERs, EGFR and Notch1 had a synergistic effect on poor prognosis of advanced NSCLC.ConclusionsThis study indicated that ERs were likely to promote NSCLC progression by modulating the integrated membrane receptor signaling network composed of EGFR, Notch1 and GSK3β/β-Catenin pathways and then affecting tumor cell behaviors. It also complemented the molecular mechanisms underlying the progression of NSCLC and provided new opportunities for optimizing therapeutic scheme of NSCLC.
Highlights
Estrogen receptors (ERs) are thought to play an important role in non-small cell lung cancer (NSCLC)
Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that ERs affected some membrane receptor signaling pathways To outline the effect of ERs in NSCLC, the gene expression data of NSCLC in TCGA database were analyzed
Using the mRNA level of ESR1, which encoded the estrogen receptor α (ERα) protein, as the phenotypic label, 1019 tumor tissue samples were divided into the high-ESR1 group (N = 509) and the low-ESR1 group (N = 510), the median value of ESR1 expression level was used as cut-off criterion
Summary
Estrogen receptors (ERs) are thought to play an important role in non-small cell lung cancer (NSCLC). ERs are important sex hormone receptors, which are proposed to affect the development and progression of lung cancer, in NSCLC. It is generally agreed that ERs are expressed both in the cytoplasm and nucleus of NSCLC cells and exert their effects through both the genomic and non-genomic mechanisms [4, 5]. There are some reports suggesting that ERs are favorable prognostic factors for NSCLC patients [12, 13]. These controversies indicate that the molecular mechanisms of ERs in NSCLC are probably more complicated than reported. We will attempt to reconsider the effect of ERs in NSCLC from a more comprehensive perspective
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