Gold Nanoparticles Inhibit PMA-Induced MMP-9 Expression via microRNA-204-5p Upregulation and Deactivation of NF-κBp65 in Breast Cancer Cells

Abstract

Objective: Breast cancer (BC) is the most common malignancy in females globally. Matrix metalloproteinase-9 (MMP-9) is crucial to the invasion, progression and spread of BC. Gold nanoparticles (AuNPs) have an anti-tumorigenic role, but their therapeutic role in microRNAs (miRNAs) regulation has not been explored. This study determined the potential of AuNPs against MMP-9 overexpression/production and miRNA-204-5p regulation in BC cells. Methods: AuNPs were newly engineered, and their stability was analyzed using the zeta potential, polydispersity index, surface-plasmon-resonance peak and transmission electron microscopy. A bioinformatics algorithm was used to predict the pairing of miRNA in the 3′untranslated-region (3′UTR) of MMP-9 mRNA. TaqMan assays were carried out to quantify miRNA and mRNA, whereas MMP-9-specific immunoassays and gelatin zymography were used to determine protein secretion and activity. The binding of miRNA in MMP-9 mRNA 3′UTR was verified by luciferase reporter clone assays and transfection with anti-miRNAs. In addition, NF-κBp65 activity was determined and confirmed with parthenolide treatment. Results: Engineered AuNPs were highly stable and spherical in shape, with a mean size of 28.3 nm. Tested in MCF-7 BC cells, microRNA-204-5p directly regulates MMP-9. AuNPs inhibit PMA-induced MMP-9 mRNA and protein via hsa-miR-204-5p upregulation. Anti-miR-204 transfected MCF-7 cells demonstrated enhanced MMP-9 expression (p < 0.001), while AuNPs treatment attenuated MMP-9 expression in a dose-dependent manner (p < 0.05). Moreover, AuNPs also inhibit PMA-induced NF-κBp65 activation in anti-hsa-miR-204 transfected MCF-7 cells. Conclusion: Engineered AuNPs were stable and non-toxic to BC cells. AuNPs inhibit PMA-induced MMP-9 expression, production and activation via NF-κBp65 deactivation and hsa-miR-204-5p upregulation. These novel therapeutic potentials of AuNPs on stimulated BC cells provide novel suggestions that AuNPs inhibit carcinogenic activity via inverse regulation of microRNAs.

Applying Cell Painting in Non-Tumorigenic Breast Cells to Understand Impacts of Common Chemical Exposures

“…PMA induces MMP-9 expression via a protein kinase Cα(PKCα)-dependent signaling cascade in BEAS-2B human lung epithelial cells (Shin et al 2007). Stimulation of MCF-7 cells with PMA significantly downregulated the expression of hsa-miR-204-5p and significantly upregulated the mRNA expression of human MMP-9 (Farhana et al 2023). An interesting future direction would be to explore whether part of Thiram’s MOA involved upregulation of MMP-9 expression.…”

Gold Nanoparticles Downregulate IL-6 Expression/Production by Upregulating microRNA-26a-5p and Deactivating the RelA and NF-κBp50 Transcription Pathways in Activated Breast Cancer Cells

“…Moreover, miRNAs are involved in the modulation of EMT, a crucial process in cancer metastasis [18,19]. Altered miRNA expression profiles have been associated with BC subtypes, clinical outcomes, and therapeutic responses [27,34,35]. Understanding the role of miRNAs in BC can provide insights into the underlying molecular mechanisms and aid in the development of diagnostic tools and targeted therapies for improved patient outcomes.…”

“…Gold nanoparticles (GNP) have gained considerable attention in medical applications due to their unique physicochemical properties and biocompatibility. These nanoscale particles, typically ranging from 1 to 100 nanometers in size, exhibit excellent stability, high surface area-to-volume ratio, and tunable optical properties [34,35]. GNP can be easily functionalized with various molecules, making them versatile platforms for targeted drug delivery, imaging, and therapy [36,37].…”

Gold nanoparticles attenuate the interferon-γ induced SOCS1 expression and activation of NF-κB p65/50 activity via modulation of microRNA-155-5p in triple-negative breast cancer cells

“…Nuclear Transcription factor, NFκB, is a potent inflammatory signaling pathway involved in numerous pathogenic processes and the treatment of cancers. Activation of NFκB signaling via its subunit p65 and/or p50 has been involved in tumorigenesis and has now been well considered one of the best targets for cancer therapy ( 61 , 62 ). This study, demonstrated a significant increase in the levels of NF-κBp65 and NF-κBp50 subunits in the nuclear extract of MDA-MB-231 cells treated with IFN-γ alone for 30 minutes.…”