ImmunoTargets and Therapy (Nov 2024)
Circ_0001944 Targets the miR-1292-5p/FBLN2 Axis to Facilitate Sorafenib Resistance in Hepatocellular Carcinoma by Impeding Ferroptosis
Abstract
FanJing Jing,1 YunYan Shi,1 Dong Jiang,2 Xiao Li,1 JiaLin Sun,1 Qie Guo1 1Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, People’s Republic of China; 2Navy Qingdao Special Service Rehabilitation Center, Qingdao, Shandong, 266003, People’s Republic of ChinaCorrespondence: Qie Guo, Email [email protected]: Sorafenib, an orally active potent tyrosine kinase inhibitor (TKI), represented a primary treatment in patients with advanced hepatocellular carcinoma (HCC). Unfortunately, sorafenib resistance was regarded as a huge obstacle for HCC treatment.Methods: RNA-sequencing including circRNA Sequencing (circRNA-Seq) for circular RNAs (circRNAs), miRNA Sequencing (miRNA-Seq) for microRNAs (miRNAs), as well as mRNA Sequencing (mRNA-Seq) for mRNAs in sorafenib-resistant HCC cells vs sorafenib-sensitive HCC cells, were performed. Then, interaction correlation analysis between differentially expressed circRNAs and miRNAs and their target genes in Huh7/SOR and SMMC7721/SOR cells was exhibited. The “circRNA-miRNA-mRNA” network was constructed through the Cytoscape software application, Circular RNA Interactome and Targetscan prediction, RNA binding protein immunoprecipitation (RIP), RNA pull-down, and Dual luciferase reporter assay. Furthermore, mRNA-Seq, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the downstream genes involved in the “circRNA-miRNA-mRNA” network was implemented. Iron detection assay, Lipid peroxidation quantification assay, ROS measurement assay, CCK-8 assay, and tumor challenge in vivo were used to determine the mechanisms promoting sorafenib resistance in HCC, where the “circRNA-miRNA-mRNA” network is clearly involved in.Results: : circ_0001944 and circ_0078607 with upregulation and 2 downregulated expressed circRNAs (circ_0002874 and circ_0069981), as well as 11 upregulated miRNAs including miR-193a-5p, miR-197-3p, miR-27a-5p, miR-551b-5p, miR-335-3p, miR-767-3p, miR-767-5p, miR-92a-1-5p, miR-92a-3p, miR-3940-3p, and miR-664b-3p and 3 downregulated expressed miRNAs (miR-1292-5p, let-7c-5p, and miR-99a-5p) in sorafenib-resistant HCC cells were determined. Among these non-coding RNAs (ncRNAs), circ_0001944 and miR-1292-5p should not be drop out of sight; circ_0001944 has been proved to target miR-1292-5p to inhibit its expression in HCC. Subsequent findings also raise that miR-1292-5p directly targeted the 3’-noncoding region (3’-UTR) of Fibulin 2 (FBLN2) mRNA. Furthermore, circ_0001944 targets the miR-1292-5p/FBLN2 axis to inhibit cell ferroptosis in which the indicated regulators associated with iron overload and lipid peroxidation were “rearranged”. Most importantly, circ_0001944 advanced sorafenib resistance in HCC through mitigating ferroptosis, where the miR-1292-5p/FBLN2 axis cannot be left unrecognized.Conclusion: : Circ_0001944 is a putative target for reversing sorafenib resistance in HCC. Our findings are expected to provide new targets and new directions for sorafenib sensitization in the treatment of HCC.Keywords: Circular RNAs, Sorafenib, hepatocellular carcinoma, MicoRNAs
