Work

Molecular and System-Level Characterization of MMP12 Suppression in Lung Cancer: A Combined Bioinformatics and Molecular Approach

Year: 2025

Type: article

Abstract: Lung cancer remains a major cause of cancer-related death, highlighting the need for new molecular targets and novel therapeutics. Matrix metalloproteinases are key regulators of invasion and microenvironment remodeling, and among them, matrix metalloproteinase-12 (MMP12) is a particularly attractive candidate whose network-level effects in cancer are still poorly defined. Herein, we applied an integrative strategy that combines bioinformatics methods with experimental validation in non-small cell lung cancer (NSCLC) cells. Protein–protein interaction (PPI) and pathway analyses of MMP12-regulated genes identified 113 downstream targets enriched in the extracellular matrix, PI3K–AKT, and immune pathways, from which an eight-gene panel (MMP12, CD44, ADAM9, NFKBIA, PSME3, SPARCL1, CCL15, and APOA1) was prioritized as a biomarker signature. Guided by these predictions, we screened a 31-compound MMP12 inhibitor library and selected five leads (C1, C7, C9, C10, and C15) for testing in H1299 cells, with C9 showing the strongest antiproliferative activity. These compounds showed antimigratory activity (C1 achieving a 90% inhibition of wound closure at its IC50 concentration), reduced clonogenic growth, cell cycle perturbation, and induction of apoptosis. Gene- and protein-expression analyses confirmed MMP12 suppression and modulation of the eight-gene panel. Upstream regulator predictions implicated reduced AKT signaling alongside an ADAM9-centered adaptive axis. Collectively, these findings highlight C1, C7, C9, C10, and C15 as promising MMP12 inhibitors, supporting their further development in preclinical lung cancer and nominating the eight-gene panel as a pharmacodynamic signature for MMP12-targeted therapies.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms262411802

Authors: Shriefa Almutairi, Rima Hajjo, Dima A. Sabbah, Kamal Sweidan, Zainab Ahmed Rashid, Sanaa K. Bardaweel

Institutions: University of Jordan, University of North Carolina at Chapel Hill, Al-Zaytoonah University of Jordan

Language: English

Topic: Protease and Inhibitor Mechanisms

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499