Deciphering the role of non-coding RNAs involved in sorafenib resistance

FanJing Jing; YunYan Shi; Dong Jiang; Xiao Li; JiaLin Sun; XiaoLei Zhang; Qie Guo

doi:10.1016/j.heliyon.2024.e29374

Deciphering the role of non-coding RNAs involved in sorafenib resistance

Heliyon. 2024 Apr 13;10(8):e29374. doi: 10.1016/j.heliyon.2024.e29374. eCollection 2024 Apr 30.

Authors

FanJing Jing¹, YunYan Shi¹, Dong Jiang², Xiao Li¹, JiaLin Sun¹, XiaoLei Zhang¹, Qie Guo¹

Affiliations

¹ Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, PR China.
² Navy Qingdao Special Service Rehabilitation Center, 266743, Qingdao, Shandong, 266003, PR China.

Abstract

Sorafenib is an important treatment strategy for advanced hepatocellular carcinoma (HCC). Unfortunately, drug resistance has become a major obstacle in sorafenib application. In this study, whole transcriptome sequencing (WTS) was conducted to compare the paired differences between non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and mRNAs, in sorafenib-resistant and parental cells. The overlap of differentially expressed ncRNAs (DENs) between the SMMC7721/S and Huh7/S cells and their parental cells was determined. 2 upregulated and 3 downregulated lncRNAs, 2 upregulated and 1 downregulated circRNAs, as well as 10 upregulated and 2 downregulated miRNAs, in both SMMC7721/S and Huh7/S cells, attracted more attention. The target genes of these DENs were then identified as the overlaps between the differentially expressed mRNAs achieved using the WTS analysis and the predicted genes of DENs obtained using the "co-localization" or "co-expression," miRanda, and RNAhybrid analysis. Consequently, the potential regulatory network between overlapping DENs and their target genes in both SMMC7721/S and Huh7/S cells was explored. The "lncRNA-miRNA-mRNA" and "circRNA-miRNA-mRNA" networks were constructed based on the competitive endogenous RNA (ceRNA) theory using the Cytoscape software. In particular, lncRNA MED17-203-miRNA (miR-193a-5p, miR-197-3p, miR-27a-5p, miR-320b, miR-767-3p, miR-767-5p, miR-92a-3p, let-7c-5p)-mRNA," "circ_0002874-miR-27a-5p-mRNA" and "circ_0078607-miR-320b-mRNA" networks were first introduced in sorafenib-resistant HCC. Furthermore, these networks were most probably connected to the process of metabolic reprogramming, where the activation of the PPAR, HIF-1, Hippo, and TGF-β signaling pathways is governed. Alternatively, the network "circ_0002874-miR-27a-5p-mRNA" was also involved in the regulation of the activation of TGF-β signaling pathways, thus advancing Epithelial-mesenchymal transition (EMT). These findings provide a theoretical basis for exploring the mechanisms underlying sorafenib resistance mediated by metabolic reprogramming and EMT in HCC.

Keywords: Circular RNAs; Hepatocellular carcinoma; Long non-coding RNAs; MicroRNAs; Non-coding RNAs; Sorafenib.