CircPVT1 Promoted the Progression of Breast Cancer by Regulating MiR-29a-3p-Mediated AGR2-HIF-1α Pathway

Background: Breast cancer (BC) is a great contributor to cancer-related death. Mounting studies have identified that circular RNAs (circRNAs) play vital roles in cancer cell proliferation, apoptosis and invasion. Here, we explored the effect of circPVT1 on BC development as well as its downstream mechanisms.

Methods: qRT-PCR was used to determine the relative expression levels of circPVT1 and miR-29a-3p in BC tissue samples and cell lines. We also analyzed the relevance between pathological indexes and circPVT1 expression level. Human breast cancer cell lines MCF-7 and MDA-MB-231 were taken as cell models. Gain- or loss-of-functional assays of circPVT1 and miR-29a-3p were conducted in BC cell lines to investigate their effects on the cell proliferation, apoptosis, migration and invasion. The protein levels of AGR2, HIF-1α, Bax, Bcl2 and Caspase3 were determined by Western blot. Furthermore, dual-luciferase reporter assay and RNA fluorescence in situ hybridization (FISH) were used to confirm the targeted relationships between circPVT1 and miR-29a-3p, miR-29a-3p and anterior gradient 2 (AGR2).

Results: CircPVT1 was highly expressed while miR-29a-3p was lowly expressed in BC tissues and cell lines. Inhibition of circPVT1 or overexpression of miR-29a-3p remarkably suppressed BC cell proliferation, invasion and migration while promoted cell apoptosis. By contrast, circPVT1 upregulation or miR-29a-3p inhibition led to mitigate malignant behaviours of BC cells. Functionally, circPVT1 bound to miR-29a-3p, and AGR2 was a target gene of miR-29a-3p. Overexpressed circPVT1 promoted AGR2 and HIF-1α expression by repressing miR-29a-3p. More importantly, overexpressing AGR2 enhances HIF-1α expression, accompanied with accelerated proliferation, invasion and migration of BC cells.

Conclusion: CircPVT1 acts as an oncogene in BC via promoting the growth, invasion, migration and inhibiting apoptosis through miR-29a-3p-mediated AGR2-HIF-1α axis.