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 whole-transcriptome 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 circRNA-miRNA-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.

 

Comments:

The study you've described investigates the mechanism underlying the action of SNX-2112, an Hsp90 inhibitor, on human melanoma A375 cells. Here's a breakdown of the key findings and their implications:

### **1. Identification of Differentially Expressed Genes:**
   - **Total Genes:** 2,528 genes were differentially expressed after SNX-2112 treatment.
   - **Upregulated Genes:** 895 genes showed increased expression.
   - **Downregulated Genes:** 1,633 genes showed decreased expression.

### **2. Enriched Pathway:**
   - **Pathway Identified:** The ECM-receptor interaction pathway was significantly enriched.
   - **Components:** This pathway involves integrins (ITGs) and collagens (COLs). ITGs are cell receptors for COLs.

### **3. Regulatory Networks:**
   - **miRNA-ITG and miRNA-COL Interactions:** 27 miRNAs were identified to interact with ITG and COL genes. Specifically, 19 upregulated miRNAs targeted downregulated ITG genes, and 8 upregulated miRNAs targeted downregulated COL genes.
   - **circRNA-miRNA-mRNA Networks:** 9 circRNAs, differentially expressed in SNX-2112-treated cells, were identified as targets of ITG- and COL-related miRNAs. This information was used to map circRNA-miRNA-mRNA regulatory networks.

### **4. Novel Regulatory Mechanism:**
   - **Discovery:** The study uncovered a novel regulatory mechanism of melanoma involving the ITG-COL network.
   - **Significance:** Understanding this mechanism provides valuable insights into how Hsp90 inhibition affects melanoma cells and offers potential targets for therapeutic intervention.

### **5. Implications and Conclusion:**
   - **Treatment Potential:** Targeting the ITG-COL network could be a promising strategy for melanoma treatment.
   - **Clinical Significance:** This research could have implications for the development of targeted therapies against melanoma, potentially improving patient outcomes.

In summary, the study highlights the significance of the ECM-receptor interaction pathway, specifically focusing on ITGs and COLs, in the context of melanoma and the impact of Hsp90 inhibition. The identified regulatory networks provide a comprehensive understanding of the molecular mechanisms at play, paving the way for further research and potential therapeutic advancements in melanoma treatment.

Related Products

Cat.No.	Product Name	Information
S2639	SNX-2112	SNX-2112 selectively binds to the ATP pocket of HSP90α and HSP90β with Ka of 30 nM and 30 nM, uniformly more potent than 17-AAG.

Related Targets

HSP (HSP90)