Circular RNA circHSPA8 Aggravates Metastasis by Acting as a Competitive Inhibitor of miR-195-5p to Upregulate WNT3A Expression in Breast Cancer

Abstract

Circular RNA (circRNA) plays a vital role in the tumorigenicity and progression of cancer by regulating various biological behaviours. It acts as a microRNA sponge, disrupting transcription and the abnormal expression of oncogenes. Hsa_circ_0024715, a circRNA generated from cyclization at specific sites of the HSPA8 gene, has been found to be highly expressed in breast cancer (BC) tissue based on non-coding RNA high-throughput sequencing. However, its functions remain poorly understood. In this study, we performed qPCR to evaluate the expression of circHSPA8 in BC tissues. Survival analysis in a prospective cohort revealed that high expression of circHSPA8 is associated with poor prognosis and lymphoid node metastasis. Overexpression of circHSPA8 in MCF-7 cells significantly enhanced their proliferative and invasive abilities, whereas knockdown of circHSPA8 in MDA-MB-231 cells significantly reduced their proliferative and invasive abilities. We found that circHSPA8 can promote epithelial-mesenchymal transition (EMT) in BC cells, primarily by upregulating the expression of WNT3A. This process depends on the sponging and inhibition of miR-195-5p, which suppresses the proliferation, invasion, and metastasis of BC cells. In vivo experiments further confirmed that circHSPA8 can promote the intravasation and extravasation of BC cells as well as the formation of metastatic lesions in the lungs. In summary, these data demonstrate that circHSPA8 promotes EMT by acting as a competitive inhibitor of miR-195-5p to upregulate the expression of WNT3A in BC, suggesting that dysregulation of circRNA in BC might be a pathological factor and potential therapeutic target.

Keywords: breast cancer; circHSPA8; circRNA; metastasis; miR‐195‐5p.