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

doi:10.3389/fonc.2021.744251

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

Front Oncol. 2021 Sep 28:11:744251. doi: 10.3389/fonc.2021.744251. eCollection 2021.

Authors

Ting Zhou^{1

2}, Mingming Li³, Zhijun Xiao², Jian Cai⁴, Weiwei Zhao⁵, Jingjing Duan², Zhen Yang⁶, Zhijun Guo², Yitian Chen², Weijia Cai², Piaopiao Huang⁷, Chaoyong He¹, Feng Xu²

Affiliations

¹ Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
² Department of Pharmacy, Fengxian Hospital, Southern Medical University, Shanghai, China.
³ Department of Pharmacy, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁴ Department of Pharmacy, Fengxian Mental Health Center, Shanghai, China.
⁵ Department of Laboratory Medicine, Fengxian Hospital, Southern Medical University, Shanghai, China.
⁶ Department of Central Laboratory, Fengxian Hospital, Southern Medical University, Shanghai, China.
⁷ Department of Pharmacy, The International Peace Maternity & Child Health Hospital of China Welfare Institute, Shanghai, China.

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.

Keywords: cancer; ceRNA network; circRNA; depression; lncRNA; microarray analysis.