Chronic Stress-Induced Gene Changes In Vitro and In Vivo: Potential Biomarkers Associated With Depression and Cancer Based on circRNA- and lncRNA-Associated ceRNA Networks.

Ting Zhou,Jian Cai,Zhen Yang,Mingming Li,Zhijun Guo,Jingjing Duan,Weijia Cai,Yitian Chen,Weiwei Zhao,Zhijun Xiao,Feng Xu,Piaopiao Huang,Chaoyong He

doi:10.3389/fonc.2021.744251

Abstract

Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) have been considered as biomarkers or regulators in many diseases. However, the exact role of circRNA- or lncRNA-mediated competing endogenous RNA (ceRNA) networks in the modulation of depression pathogenesis-relevant processes is not clear. In this study, we profiled whole transcriptome in depression patients’ blood samples via microarray analysis. As a result, a total of 340 circRNAs, 398 lncRNAs, 206 miRNAs, and 92 mRNAs were differentially expressed between the depression and control groups. Then, we constructed ceRNA networks according to the differentially expressed genes (DEGs). Using bioinformatics analysis, 89 pairs of circRNA-ceRNA and 49 pairs of lncRNA-ceRNA networks were obtained. Since depression is a broad and heterogeneous condition that is known as promoter for many chronic diseases including cancer, so we further dug out 28 circRNAs, 61 lncRNAs, 26 miRNAs, and 29 mRNAs that are associated with cancer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the DEGs were significantly enriched in cancer-related signaling pathways such as MAPK, Wnt, IL-17, Ras, and PI3K-Akt. Genes involved in the above pathways such as S100A9, GATA2, SRFP5, SLC45A3, NTRK1, FRZB, has_circ_0014221, has_circ_0014220, and has_circ_0087100 were dysregulated in various cancer cell lines by stress hormones induced. HDC, GATA2, SLC45A3, and NTRK1 were downregulated in tumor-bearing mice subjected to chronic unpredictable mild stress (CUMS). LncRNA-mediated ceRNA network validation showed that overexpression of miR-4530 declined HDC level. Our findings highlight the potential circRNA- and lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of depression and as potential biomarkers in depression cancer comorbidity through the pathways of IL-17 or histidine metabolism.

Highlights

Depression is a broad and heterogeneous condition
Since depression is known as a promoter for many chronic diseases including cancer, we further identified some cancer associated RNAs that were enriched in the IL-17 signaling pathway and histidine metabolism as the important genes, to detect their expression in various cancer cell lines induced by stress hormones as well as in tumor-bearing mice disturbed by chronic unpredictable mild stress (CUMS)
We employed the whole blood of six depression patients and six healthy controls for circRNA, long noncoding RNAs (lncRNAs), miRNA, and mRNA microarray analyses

Summary

Introduction

Depression is a broad and heterogeneous condition. About 22.1% of people worldwide suffer from depression and other mental health problems [1]. Depression is not always a separate disease, it is often accompanied by other diseases including diabetes and cancer [2, 3]. Noncoding RNAs (ncRNAs) including microRNAs (miRNAs), lncRNAs, and circRNAs play key roles in the development and progression of many diseases. CircRNAs and lncRNAs regulate gene expression via sponging miRNAs [7]. Over the past few years, remarkable progress has been made in establishing circRNAs or lncRNAs as important regulators or biomarkers of various biological processes in several diseases [2, 7,8,9,10]. Circ0093740 promotes tumor growth and metastasis by serving as a sponge of miR-136/145 [11]. The expression profiles and possible roles of these ncRNAs and their potential function in depression remain largely unknown

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