Copyright
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Analysis of long noncoding RNA-associated competing endogenous RNA network in glucagon-like peptide-1 receptor agonist-mediated protection in β cells
Li-Juan Cui, Tao Bai, Lin-Ping Zhi, Zhi-Hong Liu, Tao Liu, Huan Xue, Huan-Huan Yang, Xiao-Hua Yang, Min Zhang, Ya-Ru Niu, Yun-Feng Liu, Yi Zhang
Li-Juan Cui, Lin-Ping Zhi, Huan Xue, Huan-Huan Yang, Xiao-Hua Yang, Yi Zhang, Department of Pharmacology, Basic Medical College, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Tao Bai, Yun-Feng Liu, Department of Endocrinology, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Zhi-Hong Liu, Department of Respiratory Medicine, The First Clinical Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Tao Liu, Department of General Surgery, Shanxi Bethune Hospital, Taiyuan 030006, Shanxi Province, China
Min Zhang, College of Pharmacy, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Ya-Ru Niu, Second Clinical Medical College, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Author contributions: Bai T, Zhi LP, and Yang HH performed the experiments; Cui LJ, Xue H, Niu YR, and Zhang M performed the data analysis and interpretation; Liu T, Liu ZH, and Yang XH edited and revised the manuscript; Zhang Y and Liu YF were involved in the study design, data analysis and interpretation, manuscript composition, and manuscript editing; all authors approved the final version of the manuscript.
Supported by the National Natural Science Foundation of China, No. 81670710, No. 81770776, and No. 81973378; Cultivation of Scientific Research Excellence Programs of Higher Education Institutions in Shanxi, No. 2019KJ022; Advanced Programs of Shanxi for the Returned Overseas Chinese Scholars, No. 2016-97; Research Project Supported by the Shanxi Scholarship Council of China, No. 2017-053; FSKSC and 1331KSC, Department of Education Innovation Project in Shanxi Province, No. 2019BY078; Shanxi Youth Science and Technology Research Fund, No. 201901D211323; the Innovation and Entrepreneurship Training Program for College Students in Shanxi Province, No. 2019165; and 136 Project in Shanxi Bethune Hospital, No. 2019XY015.
Institutional review board statement: This study did not involve human studies and/or animal experiments.
Institutional animal care and use committee statement: This study did not involve human studies and/or animal experiments.
Conflict-of-interest statement: The authors declare that they have no competing interests and have nothing to disclose.
Data sharing statement: The datasets (Series GSE138744) generated and analyzed during the current study are available in the (GEO) repository, (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE138744). To review the data, please enter token: opslyaomvhmlzkb into the box. Our data in GSE138744 remains in private status now. You can review it through the pathway above, and we will make the data publicly available prior to the publication of this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Yi Zhang, PhD, Professor, Department of Pharmacology, Basic Medical College, Shanxi Medical University, No. 56 Xinjian South Road, Taiyuan 030001, Shanxi Province, China. yizhang313@163.com
Received: April 17, 2020
Peer-review started: April 17, 2020
First decision: April 22, 2020
Revised: April 24, 2020
Accepted: August 4, 2020
Article in press: August 4, 2020
Published online: September 15, 2020
BACKGROUND
Long noncoding RNAs (lncRNAs) and mRNAs are widely involved in various physiological and pathological processes. The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) is a novel therapeutic strategy that could promote insulin secretion and decrease the rate of β-cell apoptosis in type 2 diabetes mellitus (T2DM) patients. However, the specific lncRNAs and mRNAs and their functions in these processes have not been fully identified and elucidated.
AIM
To identify the lncRNAs and mRNAs that are involved in the protective effect of GLP-1RA in β cells, and their roles.
METHODS
Rat gene microarray was used to screen differentially expressed (DE) lncRNAs and mRNAs in β cells treated with geniposide, a GLP-1RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to assess the underlying functions of DE mRNAs. Hub mRNAs were filtered using the STRING database and the Cytoscape plugin, CytoHubba. In order to reveal the regulatory relationship between lncRNAs and hub mRNAs, their co-expression network was constructed based on the Pearson coefficient of DE lncRNAs and mRNAs, and competing endogenous RNA (ceRNA) mechanism was explored through miRanda and TargetScan databases.
RESULTS
We identified 308 DE lncRNAs and 128 DE mRNAs with a fold change filter of ≥ 1.5 and P value < 0.05. GO and KEGG pathway enrichment analyses indicated that the most enriched terms were G-protein coupled receptor signaling pathway, inflammatory response, calcium signaling pathway, positive regulation of cell proliferation, and ERK1 and ERK2 cascade. Pomc, Htr2a, and Agtr1a were screened as hub mRNAs using the STRING database and the Cytoscape plugin, CytoHubba. This result was further verified using SwissTargetPrediction tool. Through the co-expression network and competing endogenous (ceRNA) mechanism, we identified seven lncRNAs (NONRATT027738, NONRATT027888, NONRATT030038, etc.) co-expressed with the three hub mRNAs (Pomc, Htr2a, and Agtr1a) based on the Pearson coefficient of the expression levels. These lncRNAs regulated hub mRNA functions by competing with six miRNAs (rno-miR-5132-3p, rno-miR-344g, rno-miR-3075, etc.) via the ceRNA mechanism. Further analysis indicated that lncRNA NONRATT027738 interacts with all the three hub mRNAs, suggesting that it is at a core position within the ceRNA network.
CONCLUSION
We have identified key lncRNAs and mRNAs, and highlighted here how they interact through the ceRNA mechanism to mediate the protective effect of GLP-1RA in β cells.
Core Tip: This study investigated the long noncoding RNA (lncRNA) regulatory network involved in the protective effects of geniposide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), in pancreatic β cells using a microarray. We identified key lncRNAs and mRNAs, and highlighted how they interact through the competing endogenous RNA mechanism to mediate GLP-1RA-mediated protection in β cells. Our study has contributed to a deeper understanding of the molecular mechanism of β cell protection by GLP-1RA at the transcriptional level.
