PAX5-miR-142 feedback loop promotes breast cancer proliferation by regulating DNMT1 and ZEB1

BackgroundBreast cancer is one of the most common malignancies occurred in female around the globe. Recent studies have revealed the crucial characters of miRNA and genes, as well as the essential roles of epigenetic regulation in breast cancer initiation and progression. In our previous study, miR-142-3p was identified as a tumor suppressor and led to G2/M arrest through targeting CDC25C. However, the specific mechanism is still uncertain.MethodsWe identified PAX5 as the upstream regulator of miR-142-5p/3p through ALGGEN website and verified by series of assays in vitro and in vivo. The expression of PAX5 in breast cancer was detected by qRT-PCR and western blot. Besides, bioinformatics analysis and BSP sequencing were performed to analyze the methylation of PAX5 promoter region. Finally, the binding sites of miR-142 on DNMT1 and ZEB1 were predicted by JASPAR, and proved by luciferase reporter assay, ChIP analysis and co-IP.ResultsPAX5 functioned as a tumor suppressor by positive regulation of miR-142-5p/3p both in vitro and in vivo. The expression of PAX5 was regulated by the methylation of its promoter region induced by DNMT1 and ZEB1. In addition, miR-142-5p/3p could regulate the expression of DNMT1 and ZEB1 through binding with their 3'UTR region, respectively.ConclusionIn summary, PAX5-miR-142-DNMT1/ZEB1 constructed a negative feedback loop to regulate the progression of breast cancer, which provided emerging strategies for breast cancer therapy.

Automated summary

This study identified PAX5 as the upstream regulator of miR-142-5p/3p and demonstrated that PAX5 functions as a tumor suppressor by positively regulating miR-142-5p/3p. The expression of PAX5 is regulated by DNMT1 and ZEB1-mediated methylation of its promoter region. Moreover, miR-142-5p/3p regulates the expression of DNMT1 and ZEB1 by binding to their 3'UTR region, respectively. In conclusion, PAX5-miR-142-DNMT1/ZEB1 forms a negative feedback loop to regulate the progression of breast cancer.