Abstract B028: Unraveling the role of matrix metalloproteinase 3 (mmp3) in cisplatin resistance of ovarian cancer

Abstract Seventy percent of women with ovarian cancer will develop chemotherapy-resistance to cisplatin. Regardless of the advancements in technology, mortality rates for ovarian cancer have declined only slightly in the last forty years. Therefore, novel and effective second-line therapies for women with ovarian cancer are urgently needed. Previously we showed that Matrix Metalloproteinase 3 (MMP3) expression is upregulated in cisplatin resistant when compared with cisplatin sensitive cells. However, the contribution of MMP3 to cisplatin resistance have not been studied previously. Western blots, ELISAs, and real-time RT-PCR confirmed that the protein and mRNA levels are higher in cisplatin resistant as compared with cisplatin sensitive cells. MMP3 expression levels were also increased by cisplatin treatment of cisplatin resistant cells. Additionally, interrogation of the Kaplan-Meier plotter database showed that ovarian cancer patients with low MMP3 levels live longer than patients with higher MMP3 levels. To understand the impact of targeting MMP3, we employed commercially available chemical inhibitors and small-interference RNA (siRNA) in cell viability, colony formation, invasion, and RNAseq experiments. Notably, MMP3-targeted siRNA significantly reduced cell viability, proliferation, and invasion, particularly when combined with cisplatin treatment. However, the MMP3 chemical inhibitor did not exhibit significant biological effects. RNAseq analysis revealed 415 differentially expressed genes (DEGs) between MMP3-siRNA and negative control (NC) -siRNA groups, as well as 440 DEGs between MMP3-siRNA + cisplatin and NC-siRNA + cisplatin groups. Functional enrichment analysis using Metascape via Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) identified genes associated with potassium and aquaporin mediated transport, clathryn-mediated endocytosis, cell cycle, metabolic processes, cellular response to stress, and extracellular matrix organization. These findings highlight the role of MMP3 upregulation in promoting cisplatin resistance. Citation Format: Mariela Rivera-Serrano, Pablo E. Vivas-Mejía. Unraveling the role of matrix metalloproteinase 3 (mmp3) in cisplatin resistance of ovarian cancer abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr B028.