Analysis of the Matrix Metalloproteinases Family Profile in Gastric Cancer Suggests Key Matrix Metalloproteinases for Tumor Development and Their Clinical Impact

Gastric cancer (GC) is the fifth most common type worldwide, representing a public health problem. Among the genes related to this tumorigenesis, the family of matrix metalloproteinases (MMPs), essential regulators of the extracellular matrix (ECM), stand out for their involvement in the development and progression of GC. Therefore, we aimed to evaluate MMP gene expression variation, its relationship with clinicopathological factors and its transcriptome-wide associations. To this end, RNAseq, correlation network, and biological pathway enrichment analyses were performed on tumor samples from GC and peritumoral samples from patients treated at a reference center in the Northern region of Brazil. Among the 22 investigated MMPs, seven genes (MMP2, MMP3, MMP10, MMP12, MMP14, MMP15, and MMP16) were upregulated in cancer, while MMP8 was downregulated. Increased expression of seven of the eight differentially expressed MMPs was found in early stages of the disease compared to Tumor, Node, Metastasis (TNM) stage IV. MMP16 showed higher expression in the diffuse-type gastric adenocarcinoma. An increased expression of MMP10 was observed in the EBV/TCGA group. A significant reduction in survival was noticed in those patients with lower expression of MMP8, MMP12, and MMP14. Transcriptomic correlation analyses demonstrated that differentially expressed MMPs interact with genes likely involved in cell adhesion, ECM organization, and immune response, such as COL1A2, CDH11, KIRREL1, PPP1R14D, CEACAM8, ZNF423, and PRRX1. The enrichment of biological pathways suggests involvement in processes such as ECM organization, collagen and proteoglycan degradation, suggesting that these genes possibly are involved in carcinogenic dynamics, supporting the role of MMPs in tumor ECM reorganization.