Co-delivery of JQ1 and Gambogic acid through tumor-targeting PEGylated nanographene oxide with FSH beta peptide (33–53) identifies SNHG7-hsa-miR-324-3p-SMAD2 axis as a prognostic biomarker in ovarian cancer

Abstract

Gynecological malignancies including ovarian cancer have high mortality rates. The present work investigates if pGO-FSH-JQ1-Gambogic acid (GA) nanoparticles can target FSH-overexpressing ovarian cancer cells. The synergistic anti-ovarian cancer activity of JQ1, a bromodomain inhibitor, and Gambogic acid, were tested and assessed for cell proliferation, apoptosis, anti-angiogenic properties, and gene expression modulation. MTT, in ovo-CAM, annexin V-/PI, and live/dead cell assays using AO/ETBR staining showed that pGO-FSH-GA-JQ1 nanoparticles caused dose-dependent cell death and apoptosis, in Caov-3 cells after 48 h. Additionally, the FSH β 33–53 peptide specifically targeted FSHR in ovarian cancer cells, resulting in enhanced apoptosis. Whole transcriptome sequencing showed significantly downregulated gene expression of several critical genes implicated in ovarian cancer progression, including SMAD2. Quantitative real-time PCR confirmed that the pGO-FSH-GA-JQ1 nanoparticles altered gene expression of TGFβ pathway genes (SMAD2, SMAD4, TGFBRII, and SIN3A), associated genes (CTNNB1 and FOS), angiogenesis marker (VEGFB), cell proliferation marker (CDK6), and EMT regulating marker (CCNG2). A novel axis, SNHG7/hsa-miR-324–3p/SMAD2, targeted by JQ1 and GA, was also found using whole transcriptome sequencing and bioinformatics analysis. This novel axis may be a predictive factor for ovarian cancer treatment efficacy. Experimental results suggest that pGO-FSH-JQ1-GA nanoparticles may be an effective and synergistic ovarian cancer-targeted therapy.