MMP-12

Official Full Name

matrix metallopeptidase 12

Organism

Homo sapiens

GeneID

4321

Background

This gene encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease degrades soluble and insoluble elastin. This gene may play a role in aneurysm formation and mutations in this gene are associated with lung function and chronic obstructive pulmonary disease (COPD). This gene is part of a cluster of MMP genes on chromosome 11. [provided by RefSeq, Jan 2016]

Synonyms

MMP12; ME; HME; MME; MMP-12;

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Detailed Information

Matrix metalloproteinases (MMPs) are a class of proteolytic enzymes containing zinc ions and calcium ions that degrade extracellular matrix (ECM) components, including basement membrane collagen, interstitial collagen, fibrin and various proteoglycans. It plays a central role in inducing tumor angiogenesis, cell migration, proliferation, apoptosis and connective tissue degradation. MMP-12 was first discovered in mouse peritoneal macrophage media in 1975 and was produced by macrophages and was also the first metalloproteinase recognized to promote elastin degradation.

MMP-12 Function

MMP-12 has a wide range of substrate specificities. In addition to degrading elastin, MMP-12 also degrades many ECM ingredients, such as type I gelatin, type IV collagen, chondroitin sulfate, laminin, alpha 1 antitrypsin, and plasminogen. MMP-12 also has powerful ECM remodeling properties that can participate in the inflammatory response by activating tumor necrosis factor alpha. In addition, MMP-12 can also participate in the inflammatory process by promoting the production of neutrophil accumulation, cytokines and chemokines. MMP-12 is involved in the pathogenesis of many diseases, such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, atherosclerosis, cerebral infarction, and many tumor lesions.

MMP-12 Figure 1. Antiviral function of MMP-12.（Dandachi, N. G. , et al. 2014）

MMP-12 and Tumor

Tumor infiltration and metastasis are key steps in the progression of malignant tumors, including ECM and basement membrane degradation and tumor angiogenesis. MMP-12 can degrade ECM and vascular wall components, thereby promoting tumor cell invasion and metastasis, and MMP-12 can Activate other MMPs to promote the hydrolysis process. Studies have shown that high expression of MMP-12 is observed in epithelial cells transformed by skin cancer and vulvar cancer, and this expression is thought to be involved in dedifferentiation and invasion of epithelial cells. Heterogeneous nuclear ribonucleoprotein K can promote the invasion and metastasis of nasopharyngeal carcinoma cells by activating the MMP-12 promoter to induce MMP-12 expression and increase enzyme activity.

A study of 385 patients showed that rs2276109 polymorphism in MMP-12 is associated with metastasis and progression of colorectal cancer in Sweden, and high expression of MMP-12 may be a poor prognosis indicator for colorectal cancer. Studies have shown that compared with those with negative expression of MMP-12 in gastric cancer cells, the positive rate of MMP-12 expression is lower and the survival rate is higher. Some studies also suggest that the expression of MMP-12 in gastric cancer is a good prognostic marker. Among them, the MMP-12 expression-negative patients had lower survival rate than those with positive MMP-12 expression. MMP-12 has not been found to have a significant relationship with pancreatic cancer invasion and metastasis.

Relationship between MMP-12 and Lung Diseases

Overexpression of MMP-12 leads to pathological ECM degradation and excessive airway remodeling, promoting host immune responses and pathogenesis in some acute and chronic lung diseases, including allergic asthma, emphysema, lung cancer and lung infections. MMP-12 may be a regulator of lung injury or remodeling, as well as a marker of lung disease activity. The pathogenesis of COPD includes inflammatory mechanisms, protease-antiprotease imbalance mechanism, oxidative stress mechanism, proteases that destroy lung tissue, including macrophage elastase. Increased expression of MMP-12 promotes the degradation of elastin, disrupting lung tissue and alveolar septum, leading to emphysema. Studies have shown that MMP-12 plays a role in tobacco-induced pulmonary emphysema models. And MMP-12 is involved in small airway remodeling, which may be related to its involvement in the proteolytic process of alveolar wall matrices.

References:

Chung, I. C. , Chen, L. C. , Chung, A. K. , Chao, M. , Huang, H. Y. , & Hsueh, C. , et al. (2014). Matrix metalloproteinase 12 is induced by heterogeneous nuclear ribonucleoprotein k and promotes migration and invasion in nasopharyngeal carcinoma. BMC Cancer, 14(1), 348.
Hendrix, A. Y. , & Kheradmand, F. . (2017). The role of matrix metalloproteinases in development, repair, and destruction of the lungs. Progress in Molecular Biology & Translational Science, 148, 1.
Dandachi, N. G. , & Shapiro, S. D. . (2014). A protean protease: mmp-12 fights viruses as a protease and a transcription factor. Nature Medicine, 20(5), 470-472.

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