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

Aisha Farhana; Abdullah Alsrhani; Nazia Nazam; Muhammad Ikram Ullah; Yusuf Saleem Khan; Zafar Rasheed

doi:10.3390/biology12060777

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

Biology (Basel). 2023 May 27;12(6):777. doi: 10.3390/biology12060777.

Authors

Aisha Farhana¹, Abdullah Alsrhani¹, Nazia Nazam², Muhammad Ikram Ullah¹, Yusuf Saleem Khan³, Zafar Rasheed⁴

Affiliations

¹ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Aljouf, Saudi Arabia.
² Division of Pediatric Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
³ Department of Anatomy, College of Medicine, Jouf University, Sakaka 72388, Aljouf, Saudi Arabia.
⁴ Department of Pathology, College of Medicine, Qassim University, P.O. Box 6655, Buraidah 51452, Qassim, Saudi Arabia.

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.

Keywords: MMP-9; NF-κBp65; breast cancer; gold nanoparticles; hsa-miR-204-5p; parthenolide.

Grants and funding

DSR2022-RG -0153/Deanship of Scientific Research at Jouf University