Analysis of ceRNA networks and identification of potential drug targets for drug-resistant leukemia cell K562/ADR

Zhaoping Liu; Yanyan Wang; Zhenru Xu; Shunling Yuan; Yanglin Ou; Zeyu Luo; Feng Wen; Jing Liu; Ji Zhang

doi:10.7717/peerj.11429

Analysis of ceRNA networks and identification of potential drug targets for drug-resistant leukemia cell K562/ADR

PeerJ. 2021 May 25:9:e11429. doi: 10.7717/peerj.11429. eCollection 2021.

Authors

Zhaoping Liu^#^{1

2}, Yanyan Wang^#², Zhenru Xu³, Shunling Yuan², Yanglin Ou², Zeyu Luo⁴, Feng Wen⁴, Jing Liu⁵, Ji Zhang^{1

2}

Affiliations

¹ Department of Clinical Laboratory, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China.
² Department of Clinical Laboratory, The First Affiliated Hospital, University of South China, Hengyang, Hunan, China.
³ Department of Clinical Laboratory, The Second Affiliated Hospital, Hainan Medical University, Haikou, Hainan, China.
⁴ Department of Hematology, The First Affiliated Hospital, University of South China, Hengyang, Hunan, China.
⁵ Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.

^# Contributed equally.

Abstract

Background: Drug resistance is the main obstacle in the treatment of leukemia. As a member of the competitive endogenous RNA (ceRNA) mechanism, underlying roles of lncRNA are rarely reported in drug-resistant leukemia cells.

Methods: The gene expression profiles of lncRNAs and mRNAs in doxorubicin-resistant K562/ADR and sensitive K562 cells were established by RNA sequencing (RNA-seq). Expression of differentially expressed lncRNAs (DElncRNAs) and DEmRNAs was validated by qRT-PCR. The potential biological functions of DElncRNAs targets were identified by GO and KEGG pathway enrichment analyses, and the lncRNA-miRNA-mRNA ceRNA network was further constructed. K562/ADR cells were transfected with CCDC26 and LINC01515 siRNAs to detect the mRNA levels of GLRX5 and DICER1, respectively. The cell survival rate after transfection was detected by CCK-8 assay.

Results: The ceRNA network was composed of 409 lncRNA-miRNA pairs and 306 miRNA-mRNA pairs based on 67 DElncRNAs, 58 DEmiRNAs and 192 DEmRNAs. Knockdown of CCDC26 and LINC01515 increased the sensitivity of K562/ADR cells to doxorubicin and significantly reduced the half-maximal inhibitory concentration (IC₅₀) of doxorubicin. Furthermore, knockdown of GLRX5 and DICER1 increased the sensitivity of K562/ADR cells to doxorubicin and significantly reduced the IC₅₀ of doxorubicin.

Conclusions: The ceRNA regulatory networks may play important roles in drug resistance of leukemia cells. CCDC26/miR-140-5p/GLRX5 and LINC01515/miR-425-5p/DICER1 may be potential targets for drug resistance in K562/ADR cells. This study provides a promising strategy to overcome drug resistance and deepens the understanding of the ceRNA regulatory mechanism related to drug resistance in CML cells.

Keywords: Bioinformatics; Drug resistance; Leukemia; Long non-coding RNA; ceRNA network.

Grants and funding

This work was supported by the National Natural Science Foundation of China (Nos. 81870105 and 81770107), the Scientific Research Fund Project of Hunan Provincial Health Commission (No. 20201921), and the Scientific Research and Innovation Project of postgraduates in Hunan Province (No. CX20200970). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.