MMP-9 is a significant member of the family of MMPs, which belong to collagenase IV, widely expresses in the tissues and cells of our body, and mainly from monocytes, macrophages, neutrophils, fibroblasts, endothelial cells ,and tumor cells[13]. MMP-9’s gene locates on chromosome 20 q11.2-13.1, which is a vital component in degrading ECM and basement membrane [14]. Under normal physiological conditions, MMP-9 and TIMP work together to maintain the dynamic balance of the degradation and synthesis of ECM, and the stability of the tissue structure [15]. On the other hand, MMP-9 plays an important role in many physiological or pathological changes, such as inflammatory cells invasion and metastasis, vascular remodeling, organ fibrosis and cancer cell invasion and metastasis[16]. Under pathological conditions, the imbalance of ECM degradation and remodeling by MMP-9 affects the structure and function of various organs and cells, and changes the vascular microenvironment, thus promote the occurrence and development of various diseases [17, 18]. Researches showed that MMP-9 is related to the susceptibility and development of some cardiovascular diseases such as coronary heart diseases (CHC), atherosclerosis, digestive system diseases such as gastric cancer, colorectal cancer, some liver diseases like NAFLD, HCC etc. [19–21]. Study[22] have found that MMP-9 has multiple gene polymorphism sites, among which the − 1562 C/T (rs3918242) SNP is located at the promoter polymorphism site, and is the most widely and deeply studied SNP site. In MMP-9-1562 T allele carriers, its level and activity of MMP-9 in plasma protein are higher than C allele carriers, and which is closely related to the susceptibility of various diseases, invasion and metastasis of tumor cells, etc. [23]. Therefore, MMP-9-1562 C/T polymorphism can be used as a potential biological detection index to evaluate the efficacy and prognosis of clinical individualized treatment and monitor the treatment process.
This study conducted a meta-analysis of 7 relevant literatures to explore the relationship between MMP-9-1562 C/T gene polymorphism and liver diseases. The results showed that the TT genotype may be a risk factor for primary hepatic cancer, hepatocellular carcinoma and nonalcoholic fatty liver disease. Research[24] showed that, compared with CC genotype carriers, the mRNA level, protein level and MMP-9 activity of -1562 T allele carriers were significantly increased, not only can promote the proliferation, activation, and migration of hepatic stellate cells (HSC), but also stimulate the development of liver inflammation and fibrosis[25], leading to vascular remodeling of organs and changes of microenvironment. So we can infer that, compared with non-carriers, the MMP- 9 transcription and translation level in MMP-9-1562 T allele carriers was increased significantly, which promote the activation of HSC, and make HSC excessive secrete inflammatory factors and fibrosis factors such as IL-1, transforming growth factor (TGF-β), and platelet-derived growth factor (PDGF), which accelerate the imbalance of ECM degradation and synthesis, leading to excessive deposition of ECM in the liver, finally resulting in NAFLD from simple fatty liver to fatty liver fibrosis pathological change. At the same time, the overexpression of MMP-9 activates TGF-β /SMAD, PI3K/AKT and other signal transduction pathways, which stimulate the proliferation of HSC and inhibit its apoptosis, accelerating the invasion and metastasis of inflammatory cells or cancer cells, enhancing vascular remodeling and changes, and thus lead to the occurrence and development of primary liver cancer, hepatocellular carcinoma and other liver cancers.
There are still some limitations in this study: (1) the number of references included in this study is small, and the number of research samples is small, which limits the demonstration intensity of the results of the systematic evaluation; (2) The liver diseases included in this study refer to primary liver cancer, non-alcoholic fatty liver, liver cirrhosis, and hepatocellular carcinoma; However, there was only one reference for each of the first two diseases, so there may be some bias and cannot represent the general situation.
With the development of society, liver disease has become a clinically urgent problem to be solved. This study suggests that in MMP-9-1562 C/T gene polymorphism, the TT genotype may be one of the risk factors for PHC, HCC and NAFLD. This means that patients with NAFLD with MMP-9-1562 TT genotype may have a higher risk of developing liver cancer, so early intervention should be carried out to prevent the occurrence of liver cancer in clinical practice; active diagnosis and treatment should be carried out for patients with HCC or PLC with TT genotype, and corresponding gene therapy should be explored to improve the quality of life and prognosis of cancer patients. Therefore, in the future clinical treatment of chronic liver diseases, more in-depth researches are needed to explore the important role and mechanism of MMP-9-1562 gene polymorphism in the occurrence and development of liver diseases, so as to provide basis for individualized disease monitoring, curative effect evaluation and prognosis of liver diseases, and also provide help and new ideas for the study of liver diseases mechanism.