Identification of circRNA-miRNA-mRNA Network Regulated by Hsp90 in Human Melanoma A375 Cells

Background: Melanoma is the deadliest form of skin cancer. Heat shock protein 90 (Hsp90) is highly expressed in human melanoma. Hsp90 inhibitors can suppress the growth of human melanoma A375 cells; however, the underlying mechanism remains unclear. Methods: A375 cells were treated with SNX-2112, an Hsp90 inhibitor, for 48 h, and wholetranscriptome sequencing was performed. Results: A total of 2,528 differentially expressed genes were identified, including 895 upregulated and 1,633 downregulated genes. Pathway enrichment analyses of differentially expressed mRNAs identified the extracellular matrix (ECM)-receptor interaction pathway as the most significantly enriched pathway. The ECM receptor family mainly comprises integrins (ITGs) and collagens (COLs), wherein ITGs function as the major cell receptors for COLs. 19 upregulated miRNAs were found to interact with 6 downregulated ITG genes and 8 upregulated miRNAs were found to interact with 3 downregulated COL genes. 9 differentially expressed circRNAs in SNX-2112- treated A375 cells were identified as targets of the ITG- and COL-related miRNAs. Based on the differentially expressed circRNAs, miRNAs, and mRNAs, ITGs- and COL-based circRNAmiRNA- mRNA regulatory networks were mapped, revealing a novel regulatory mechanism of Hsp90-regulated melanoma. Conclusion: Targeting the ITG-COL network is a promising approach to the treatment of melanoma.