Regulation of Cell Function and Myeloid-Derived Suppressor Cell Chemotaxis by hsa_circ_0006466-miR-1286-PDGFRA/B Axis...

Circular RNAs (circRNAs) play critical regulatory roles in diverse biological processes of breast cancer. This study aimed to investigate the circRNAs potentially related to immunity in triple-negative breast cancer (TNBC).

We identified the dysregulated circRNAs in breast cancer using Gene Expression Omnibus (GEO) datasets. Then, their targeting microRNAs (miRNAs) were searched and overlapped with the miRNAs upstream of immune-associated genes. An immune-related circRNA-miRNA-mRNA network was constructed. Hsa_circ_0006466-miR-1286-PDGFRA/B axis was verified from perspectives of expression levels, binding relationships, cell functions, and regulation on myeloid-derived suppressor cells (MDSCs).

A total of 28 circRNAs were identified to be dysregulated and related to the immune system in TNBC. The immune-related circRNA-miRNA-mRNA network consisted of 28 circRNAs, 106 miRNAs, and 205 mRNAs. Hsa_circ_0006466 and PDGFRA/B mRNA were upregulated in TNBC patients and positively correlated with MDSC levels. miR-1286 was downregulated in TNBC patients and negatively correlated with MDSC levels. Cotransfection experiments, luciferase reporter assay, and RNA pull-down analyses confirmed hsa_circ_0006466-miR-1286-PDGFRA/B axis. Hsa_circ_0006466 inhibited TNBC cell migration/invasion and proliferation via miR-1286-PDGFRA/B. MDSC differentiation from THP-1 and chemotaxis in TNBC cell medium were moderated by hsa_circ_0006466-miR-1286-PDGFRA/B axis.

Our study identifies hsa_circ_0006466 as an immune-related circRNA in TNBC, functioning as a ceRNA to sponge miR-1286 and upregulate PDGFRA/B expression, thereby promoting MDSC-mediated immunosuppression and TNBC progression. Targeting this axis may offer a dual therapeutic strategy to suppress TNBC aggressiveness and reverse immune evasion.