In Silico Analysis of miRNA Role in Resistance of Hepatocellular Carcinoma Bel-7402 Cells to TRAIL

To this date, the exact basics of microRNAs (miRNAs) mechanisms in inducing a resistance to tumor necrosis factor –related apoptosis-inducing ligand (TRAIL) signaling pathways remain unclear.

The aim of this study was to analyze miRNA signaling pathways in TRAIL-resistant Bel-7402 cell line.

The Gene Expression Omnibus (GEO) database was studied for miRNA expression profiling studies in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells. By searching through databases of DIANAmT, miRanda, miRDB, miRWalk, and PICTAR using the online tools of miRWalk and TargetScan, target genes of miRNAs were predicted to express differentially by up to 50% in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells. Afterwards, signaling pathways and biological functions of miRNA target genes in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells were analyzed by the DAVID database.

A total of 352 miRNAs (186 up- and 166 downregulated miRNAs) were obtained from GSE74130 GEO DataSets accession item. The upregulated miRNAs including hsamir-145, hsa-mir-188, hsa-mir-221, hsa-mir-4802-5p, hsa-mir-198, hsa-mir-1184, and hsa-mir-345-3p were significantly intensified in apoptotic signaling pathway and process. The downregulated miRNAs including hsa-mir-138, hsa-mir-375, hsa-mir-449, hsa-mir-637, hsa-mir-208-3p, hsa-mir-4783-5p, hsamir-548b-3p, hsa-mir-127-3p, hsa-mir-92b-5p, hsa-mir-375, hsa-mir-503-5p, hsa-mir-499a-3p, and hsamir-154-3p were significantly raised in expression in cancer stem cell pathways.

Analysis of miRNA expression profile revealed that some of the upregulated miRNAs negatively contributed to the regulation of apoptosis signaling pathways and cell cycle arrest as well as promoting TRAIL-induced apoptosis resistance in TRAIL-resistant Bel-7402 cells. Also, down-regulated miRNAs were probably involved in cancer stem cell processing