CREBZF mRNA nanoparticles suppress breast cancer progression through a positive feedback loop boosted by circPAPD4

Abstract

Background Breast cancer (BC) negatively impacts the health of women worldwide. Circular RNAs (circRNAs) are a group of endogenous RNAs considered essential regulatory factor in BC tumorigenesis and progression. However, the underlying molecular mechanisms of circRNAs remain unclear. Methods Expression levels of circPAPD4, miR-1269a, CREBZF, and ADAR1 in BC cell lines and tissues were measured using bioinformatics analysis, RT-qPCR, ISH, and IHC. Cell proliferation and apoptosis were measured using CCK8, EdU staining, flow cytometry, and TUNEL assays. Pearson correlation analysis, RNA pull-down, dual-luciferase reporter, and co-immunoprecipitation assays were used to explore the correlation among circPAPD4, miR-1269a, CREBZF, STAT3, and ADAR1. Effects of circPAPD4 overexpression on tumor progression were investigated using in vivo assays. Moreover, CREBZF mRNA delivered by polymeric nanoparticles (CREBZF-mRNA-NPs) was used to examine application value of our findings. Results CircPAPD4 expression was low in BC tissues and cells. Functionally, circPAPD4 inhibited proliferation and promoted apoptosis in vitro and in vivo. Mechanistically, circPAPD4 biogenesis was regulated by ADAR1. And circPAPD4 promoted CREBZF expression by competitively binding to miR-1269a. More importantly, CREBZF promoted circPAPD4 expression by suppressing STAT3 dimerization and ADAR1 expression, revealing a novel positive feedback loop that curbed BC progression. Systematic delivery of CREBZF-mRNA-NPs effectively induced CREBZF expression and activated the positive feedback loop of circPAPD4/miR-1269a/CREBZF/STAT3/ADAR1, which might suppress BC progression in vitro and in vivo. Conclusion Our findings firstly illustrated that circPAPD4/miR-1269a/CREBZF/STAT3/ADAR1 positive feedback loop mediated BC progression, and delivering CREBZF mRNA nanoparticles suppressed BC progression in vitro and in vivo, which might provide novel insights into therapeutic strategies for breast cancer.

A Nanorobotics-Based Approach of Breast Cancer in the Nanotechnology Era

“…designed to counteract the main neoplastic hallmark features of BC by sustaining proliferative pathways [31,32], evading growth suppressors/evasion of anti-growth signaling [12], resisting programmed cell death [33][34][35][36][37][38][39][40][41][42], inducing angiogenesis (neovascularization) [43][44][45][46], activating invasion and metastasis [47][48][49], preventing genomic instability, mutation, mitosis/cell cycle deregulation [50], evading/avoiding immune destruction [51] and deregulating autophagy [52,53].…”

“…Circular RNAs (circRNAs) act as microRNA sponges and regulate gene expression as they are related to the hallmarks of cancer-sustaining signaling pathways, including invasion, recurrence, metastasis, apoptosis, ferroptosis and treatment resistance [117]. Zhou et al (2023) showed that delivering CREBZF mRNA NPs can inhibit BC proliferation and promote apoptosis in both BC tissues and cell lines [32]. These authors have proposed a new circRNA, called circPAPD4, whose expression is low in BC tissues and cells, that acts as a sponge by binding miRNA-1269a to increase the expression of CREBZF, a transcription factor that inhibits the activation of STAT3 pathway, leading to a reduction in cell cycle progression [32].…”

“…In this review, readers will be able to deepen their knowledge of the structure, behavior and role of nanorobots, among other nanomaterials, in BC theranostic. We have summarized here the characteristics of several functionalized nanodevices that have been designed to counteract the main neoplastic hallmark features of BC by sustaining proliferative path-ways [31,32], evading growth suppressors/evasion of anti-growth signaling [12], resisting programmed cell death [33][34][35][36][37][38][39][40][41][42], inducing angiogenesis (neovascularization) [43][44][45][46], activating invasion and metastasis [47][48][49], preventing genomic instability, mutation, mitosis/cell cycle deregulation [50], evading/avoiding immune destruction [51] and deregulating autophagy [52,53].…”

Functions of Circular RNA in Human Diseases and Illnesses

“…Development of breast cancer in vivo and in vitro was found to be suppressed when introducing CREBZF mRNA nanoparticles. This contributes to new understandings of therapeutic approaches for breast cancer [ 126 ]. The mRNA translation and stability could be modulated by miRNAs binding to target mRNAs creating a complex with a protein known as Argonaute (AGO) protein [ 127 ].…”

Correction: CREBZF mRNA nanoparticles suppress breast cancer progression through a positive feedback loop boosted by circPAPD4

“…Following publication of the original article [ 1 ], an error was identified in the author list. Authors, Boxuan Zhou, Jinhua Xue, Runxin Wu, Hongyu Meng, and Ruixi Li were not recognized as equal contributors and co-first authors.…”