砷剂处理的小鼠心肌全转录组分析与 circRNA-lncRNA 网络构建。

The whole transcriptome analysis and the circRNA-lncRNA network construction in arsenic trioxide-treated mice myocardium.

机构信息

Department of Pharmacology (State-Province Key Laboratories of Biomedicine, Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China; College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.

出版信息

Biomed Pharmacother. 2022 Jul;151:113183. doi: 10.1016/j.biopha.2022.113183. Epub 2022 May 27.

DOI:10.1016/j.biopha.2022.113183

PMID:35676786

Abstract

BACKGROUND/AIMS: Arsenic trioxide (ATO) is an effective anti-cancer drug. Nonetheless, it possesses cardiotoxic effects which limit its clinical application. The present study aims to elucidate the molecular basis of ATO-induced cardiotoxicity through using whole transcriptome analysis.

METHODS

The whole transcriptome in ATO-treated mice myocardium was analyzed using RNA sequencing technique. These results were confirmed by real-time PCR. The lncRNA-mRNA and circRNA-mRNA co-expression networks were constructed. Finally, a circRNA-lncRNA co-regulated competing endogenous RNA (ceRNA) network was constructed. GO and KEGG pathway analyses were performed. The expression levels of Txnip and Spp1 in ATO-treated neonatal mouse cardiomyocytes were validated by real-time PCR.

RESULTS

A total of 113 mRNAs, 159 lncRNAs, 35 miRNAs, and 94 circRNAs were differentially expressed in ATO-treated mice myocardium. A lncRNA-circRNA co-regulation network was constructed. Function annotation revealed that aberrantly expressed genes may be enriched in the 'Wnt signaling pathway', 'Hippo signaling pathway', 'Notch signaling pathway', etc. Finally, the expression levels of Txnip and Spp1 were validated in ATO-treated cardiomyocytes, which was in accordance with the RNA-sequencing results.

CONCLUSION

ATO altered coding and noncoding RNA profiles in myocardium of mice. The ATO-related lncRNA-circRNA co-regulation network was constructed. Genes in the co-regulation network are likely to play important roles in the cardiotoxicity of ATO. This study provides new insights into the prevention and treatment of ATO-induced cardiotoxicity.

摘要

背景/目的：三氧化二砷（ATO）是一种有效的抗癌药物。然而，它具有心脏毒性作用，限制了其临床应用。本研究旨在通过全转录组分析阐明 ATO 诱导的心脏毒性的分子基础。

方法

使用 RNA 测序技术分析 ATO 处理的小鼠心肌中的全转录组。这些结果通过实时 PCR 进行了验证。构建了 lncRNA-mRNA 和 circRNA-mRNA 共表达网络。最后，构建了 circRNA-lncRNA 共调控竞争性内源性 RNA（ceRNA）网络。进行了 GO 和 KEGG 通路分析。通过实时 PCR 验证了 ATO 处理的新生小鼠心肌细胞中 Txnip 和 Spp1 的表达水平。

结果

ATO 处理的小鼠心肌中共有 113 个 mRNAs、159 个 lncRNAs、35 个 miRNAs 和 94 个 circRNAs 表达差异。构建了 lncRNA-circRNA 共调控网络。功能注释表明，异常表达的基因可能富集在“Wnt 信号通路”、“Hippo 信号通路”、“Notch 信号通路”等通路中。最后，验证了 ATO 处理的心肌细胞中 Txnip 和 Spp1 的表达水平，与 RNA-seq 结果一致。