Matrix metalloproteinases (MMPs) are a large family of zinc endopeptidases that play important roles in a variety of physiological and pathological processes. These enzymes are widely distributed in all kingdoms of life and may have evolved from single-domain proteins that have undergone continuous repeated replications, gene fusions and exon shuffling events to generate the multi-domain structure currently exhibited by MMP and Functional diversity. Proper regulation of these enzymes is needed to prevent their harmful activities in a variety of diseases, including cancer, arthritis, and cardiovascular disease. Although the tissue specificity of multiple family members is primarily achieved by combining different transcriptional control mechanisms, multiple hormones, cytokines, and growth factors can induce MMP expression. The integration of multiple signaling pathways and the synergy between several cis-regulatory elements found at the MMP promoter have promoted strict spatiotemporal control of MMP transcriptional activity. In addition, epigenetic mechanisms, such as DNA methylation or histone acetylation, may also contribute to MMP regulation. Similarly, post-transcriptional regulatory processes (including mRNA stability, protein translation efficiency, and microRNA-based mechanisms) have recently been described as regulators of MMP gene expression. Parallel studies have led to the identification of MMP polymorphisms and mutations that may be related to the development of different genetic diseases. These genomic analyses have been further expanded by generating animal models of gain or loss of MMP function that allow the identification of new functions of these enzymes and the establishment of a causal relationship between MMP disorders and the development of different human diseases. Further genomic studies of MMPs, including functional analysis of gene regulation and the creation of new animal models, will help answer many of the outstanding questions related to the family of enzymes that have a major impact on multiple events in life and disease.
Figure 1. Structure of the MMP protein.
MMPs can almost degrade various protein components in ECM, destroy the histological barrier of tumor cell invasion, play a key role in tumor invasion and metastasis, and thus play an increasingly important role in tumor invasion and metastasis, which is considered to be the main process in this process. Proteolytic enzymes. The MMPs family has isolated 26 members, numbered MMP1-26. According to the substrate and fragment homology, MMPs are classified into 6 classes, which are collagenase, gelatinase, matrix degrading factor, matrix lysin, furin-activated MMP and other secreted MMPs.
Type IV collagenase is an important one of them. It has two main forms, one is saccharified, the molecular weight is 92kD, named MMP2, and the other is non-saccharified, with a molecular weight of 72kD, called MMP2. The current research on MMP2 and MMP2is more in-depth. The MMP2 gene is located on human chromosome 16q21 and consists of 13 exons and 12 introns. The total length of the structural gene is 27 kb. Unlike other metalloproteinases, the 5' flanking sequence promoter region of MMP2 gene contains 2 GC boxes instead of TATA boxes. The activated MMP2 is localized to the prominent part of the cell penetrating matrix, and it is estimated that it has a "drill" role in enzymatic hydrolysis of the intercellular matrix component and the main component of the basement membrane type IV collagen. In addition, MMP3 and MMP-10 have been shown to act on PG, LN, FN, type III and type IV collagen and gelatin. And MMP3 is able to activate MMP-1 and other family members. MMP7 acts on gelatin and FN. MMP-1 is produced in a wide range and can be produced by matrix fibroblasts, macrophages, endothelial cells, and epithelial cells. Under normal circumstances, the positive rate of MMP-1 is very low, but it can be highly expressed under various stimuli. Studies have shown that high expression of MMP-1 in malignant tumors is associated with prognosis. The activity of MMPs is regulated by three levels, namely, the level of gene transcription, the activation of inactive enzyme precursors by proteolysis, and the action of specific inhibitory factors (TIMPs).
Figure 2. Structure of the MMP10 protein.
Role in cancer
MMP7 was found to be involved in tumor metastasis and inflammatory processes. Upregulation of MMP7 is associated with many malignancies, including esophageal cancer, gastric cancer, colon cancer, liver cancer, pancreatic cancer, and renal cell carcinoma. High expression of MMP7 promotes cancer invasion and angiogenesis by degrading extracellular matrix macromolecules and connective tissue. These degradations are associated with a number of mechanisms including embryogenesis, postpartum uterine involution, tissue repair, angiogenesis, bone remodeling, arthritis, hemorrhoid ulcers, and tumor metastasis/invasion. Activated MMP7 activates MMP2 and MMP2 zymogens and mediates proteolytic processes of tumor necrosis factor and urokinase plasminogen activator precursors.
Figure 3. Structure of the MMP2 protein.