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Identification of circRNA-miRNA-mRNA Network Regulated by Hsp90 in Human Melanoma A375 Cells
Qiang Fu1, Hengyuan Gao1, Kaisheng Liu1
1Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
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.
Insights
Heat shock protein 90 (Hsp90) inhibitors suppress melanoma growth by altering extracellular matrix interactions. Targeting integrins and collagens offers a promising new melanoma treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Melanoma, the deadliest skin cancer, exhibits high expression of Heat Shock Protein 90 (Hsp90).
- Hsp90 inhibitors show potential in suppressing melanoma cell growth, but the mechanisms are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which Hsp90 inhibitors affect melanoma cell growth.
- To identify key molecular pathways and regulatory networks involved in Hsp90 inhibition in melanoma.
Main Methods:
- Whole-transcriptome sequencing was performed on A375 melanoma cells treated with the Hsp90 inhibitor SNX-2112.
- Differential gene expression analysis, pathway enrichment, and regulatory network mapping (circRNA-miRNA-mRNA) were conducted.
Main Results:
- Treatment with SNX-2112 resulted in 2,528 differentially expressed genes, significantly enriching the extracellular matrix (ECM)-receptor interaction pathway.
- Integrins (ITGs) and collagens (COLs) were identified as key components of the affected pathway, with specific miRNA interactions noted.
- Novel circRNA-miRNA-mRNA regulatory networks involving ITGs and COLs were constructed, revealing a new Hsp90-mediated regulatory mechanism in melanoma.
Conclusions:
- The study identified a novel regulatory mechanism of Hsp90 in melanoma involving circRNA-miRNA-mRNA networks centered on the ITG-COL pathway.
- Targeting the integrin-collagen network presents a promising therapeutic strategy for melanoma treatment.
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