Abstract
BackgroundThe involvement of circular RNAs (circRNAs) in tamoxifen (TAM) resistance has been identified. Herein, we aimed to identify the role and novel mechanisms of hsa_circ_0025202 in tamoxifen resistance in breast cancer (BC).MethodsThe levels of hsa_circ_0025202, microRNA (miR)-197-3p, and homeodomain-interacting protein kinase 3 (HIPK3) were tested using quantitative real-time polymerase chain reaction and western blot. IC50 value of TAM, cell proliferation, cell cycle, cell invasion, migration, apoptosis, western blot, and mouse xenograft assays was used to demonstrate the effects of hsa_circ_0025202, miR-197-3p, and HIPK3 on BC cell tumorigenesis and TAM resistance. Dual-luciferase report and RNA immunoprecipitation assays were applied to explore the potential interaction between miR-197-3p and hsa_circ_0025202 or HIPK3.ResultsHsa_circ_0025202 was decreased in BC tissues and TAM resistant BC cells, and knockdown of hsa_circ_0025202 elevated the IC50 value of cells to TAM, led to the promotion of cell proliferation, invasion and migration, mediated cell cycle progression, and inhibited cell apoptosis in BC in vitro. Besides, the upregulation of hsa_circ_0025202 hindered tumor growth and promoted TAM sensitivity in vivo. In a mechanical study, hsa_circ_0025202 targeted miR-197-3p, and silencing of miR-197-3p reversed the regulatory effects of hsa_circ_0025202 knockdown on TAM resistance and malignant phenotypes. Additionally, HIPK3 was a target of miR-197-3p, and miR-197-3p overexpression enhanced TAM resistance and promoted cell malignant biological behaviors in BC by targeting HIPK3.ConclusionHsa_circ_0025202 repressed cell tumorigenesis and TAM resistance via miR-197-3p/HIPK3 axis in BC, suggesting a potential therapeutic strategy to overcome chemoresistance in BC patients.
Highlights
IntroductionThe involvement of circular RNAs (circRNAs) in tamoxifen (TAM) resistance has been identified
The involvement of circular RNAs in tamoxifen (TAM) resistance has been identified
MiR-197-3p is a target of hsa_circ_0025202 In breast cancer (BC) tissues, we found miR-197-3p was upregulated compared with the non-tumor tissues (Fig. 4a); besides, its expression was higher in T47D and MCF7 cells, in particular in TAM-resistant BC cell lines (T47D/TAM and MCF7/TAM), than that in normal
Summary
The involvement of circular RNAs (circRNAs) in tamoxifen (TAM) resistance has been identified. We aimed to identify the role and novel mechanisms of hsa_circ_0025202 in tamoxifen resistance in breast cancer (BC). CircRNAs often show species-, tissue-, and cell-specific expression patterns and have been implicated in multiple cellular crucial biological processes related to tumorigenesis and drug sensitivity [10,11,12]. Knockdown of circBMPR2 promoted cell tamoxifen resistance and malignant biological behaviors in BC via regulating miR553/ubiquitin-specific protease 4 axis [14]. Hsa_circ_0025202 is a newly identified circRNA, generated from the back-splicing of glyceraldehyde 3phosphate dehydrogenase (GADPH) gene. Hsa_circ_0025202 have been found to inhibit BC progression and tamoxifen resistance by repressing miR182-5p-meidated FOXO3a suppression, suggesting the anti-oncogenic role of hsa_circ_0025202 in BC [15]. Large-scale identification of hsa_circ_0025202 in chemoresistant BC cells was not yet reported
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