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

Abstract

Background Breast 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. Methods We 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. Results PAX5 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. Conclusion In 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.

Exploring the oncogenic potential of circSOD2 in clear cell renal cell carcinoma: a novel positive feedback loop

“…PAX5, the gene encoding paired box 5, is specifically upregulated in many cancers, including diffuse large B-cell lymphoma [ 39 ], breast cancer [ 40 ], glioblastoma [ 41 ], and pancreatic cancer [ 42 ]. However, the regulatory mechanism of PAX5 in ccRCC has not been explored.…”

miR‐142‐3p/5p role in cancer: From epigenetic regulation to immunomodulation

“…The miR-142 level is reduced in breast cancer cells and has a central role in tumor progression. 32 In vitro and in vivo analysis indicated that downregulation of miR-142 leads to the increases of DNMT1 levels and consequently hypermethylation of PAX5 (Paired Box 5) promotor, a tumor suppressor gene. On the other hand, PAX5 acts as the upstream modulator of miR-142 in the positive feedback loop.…”

miR-142: A Master Regulator in Hematological Malignancies and Therapeutic Opportunities

“…This interaction forms an epigenetic loop involving miRNA. Epigenetic control of miR-142 has been identified as a contributing factor to malignant phenotypes in cancers such as glioblastoma, nasopharyngeal carcinoma, and breast cancer [ 339 , 340 , 341 , 342 ]. Investigating the effect of miR-142 on epigenetic enzymes and the role of miR-142 in epigenetic control loops, specifically in hematological malignancies, could not only deepen our understanding of miR-142 mechanisms in lymphomagenesis and leukemogenesis but also provide valuable clinical targets.…”