Numerous studies have suggested that dysregulation of MMPs is involved in the development and progression of many tumors. Although some members of MMPs have been shown to play crucial roles in carcinoma, the distinct roles of MMP family members in UVM remain to be elucidated. In this study, the mutations, mRNA expression, prognostic values, and potential functions of different MMP family members in UVM were identified with bioinformatics tools.
MMP proteins are associated with the breakdown of the extracellular matrix during physiological processes and disease processes. Mutations in MMP1 are associated with chronic obstructive pulmonary disease [32]. Moreover, recent studies have shown that MMP1 is highly expressed in human oral squamous cell carcinoma and cervical squamous cell carcinoma. It can promote tumor growth and cell motility, participate in the development of human oral squamous cell carcinoma [33], and serve as a potential biomarker for cervical squamous cell carcinoma [12]. In our study, MMP1 was found to be upregulated in UVM tissues, and high expression indicated shorter OS and DFS, which was consistent with the results of previous studies.
MMP2 is a zinc-dependent enzyme that cleaves the components of the extracellular matrix and molecules. Unlike most MMP family members, activation of MMP2 occurs on the cell membrane. This enzyme can be activated extracellularly and intracellularly and is involved in multiple pathways. Mutations in this gene are associated with the Winchester syndrome [34]. Recent studies have indicated that MMP2 is highly expressed in many tumors, and its increase promotes proliferation and metastasis, and reduces tumor cell apoptosis [35–37]. In our study, MMP2 was found to be upregulated in UVM, and high expression indicated shorter OS and DFS.
Like other MMP family members, MMP9 is involved in disease processes such as metastasis and arthritis, as well as in the degradation of extracellular matrix components in normal processes such as reproduction and tissue remodeling. MMP9 has been found to play an essential role in cancer progression and is significantly associated with metastasis, angiogenesis, and tumor growth [38]. Dysregulation of MMP9 is involved in various diseases, such as neurological disorders [39], inflammatory diseases [40], cardiovascular diseases [16], and lung diseases [8]. In our study, MMP9 was found to be upregulated in UVM, and high expression indicated shorter OS and DFS, which was consistent with the results of previous studies.
MMP11 is a protein-coding gene, and MMP25 is an important paralog of this gene. MMP11, a zinc-dependent endopeptidase and the main protease involved in ECM degradation, plays an important role in various biological processes, such as breast cancer[13], prostate cancer[9], gastric cancer [41], and lung cancer [42], where the high expression of MMP11 is associated with metastasis and a poor clinical outcome. Furthermore, several studies have shown that MMP11
is a potential biomarker gene in breast cancer, which may facilitate the diagnosis and prognosis of breast cancer [43, 44]. In our study, MMP11 was found to be upregulated in UVM, and high expression indicated shorter OS and DFS, which was consistent with the results of previous studies.
The protein encoded by MMP14 is a member of the membrane-type MMP(MT-MMP), which contains a potential transmembrane domain, indicating that it is expressed on the cellular surface.
Studies have reported that high MMP14 expression is associated with poor prognosis and might serve as a marker of progression in muscle-invasive bladder cancer and colorectal cancer [10, 45]. Low MMP14 expression can inhibit the invasion and metastasis of breast cancer and gastric cancer cells [46, 47]. In our study, MMP14 was found to be upregulated in UVM, and high expression indicated shorter DFS, but it was not associated with OS in patients with UVM.
Like MMP14, the protein encoded by MMP15 is also a member of the MT-MMP. MMP15, also known as MT2-MMP, was first extracted from a human lung cDNA library.
It is composed of 669 amino acids encoded in 3,530 bp of the gene. Proteins in this family are associated with the breakdown of the extracellular matrix in various diseases. MMP15 is highly expressed in bladder cancer and contributes to inflammation and angiogenesis in cancer cells [48]. MMP15 is also associated with malignancy, aggressiveness, and survival prognosis in human urinary bladder cancer by activating other MMPs [49]. The expression of MMP15 is significantly higher in tumors with a higher level of aggressiveness and malignancy [15]. In our study, MMP15 was not found to be upregulated in UVM and the expression of MMP15 was not associated with OS or DFS in patients with UVM.
MMT16 was once referred to as MT-MMP2 and is has been renamed as MT-MMP3 or MMP16.
MMP16 is activated when cleaved by other proteinases. Degradation of extracellular and microRNAs in cancer is an important pathway related to MMP16. MMP24 is an important paralog of the MMP16 gene. Some studies have indicated that high expression of MMP16 is associated with the proliferation, migration, and invasion of cutaneous squamous cell carcinoma cells [50], while knockdown of MMP16 could inhibit cell proliferation and invasion in chordoma cells [11]. Moreover, some variations in MMP16 have been found to be associated with different types of diseases [51, 52]. In our study, MMP16 was found to be upregulated in UVM, and high expression was associated with shorter OS and DFS.
MMP17 is a protein-coding gene that is associated with diseases such as breast cancer [14], colon cancer [53], and head and neck cancer [54]. While the expression of MMP17 has been associated with different physiological and pathological processes, the mechanisms underlying these processes remain unknown. In our study, MMP17 was not found to be upregulated in UVM and the expression of MMP17 was not associated with OS and shorter DFS in UVM.
The MMP24 protein is associated with the breakdown of the extracellular matrix in disease processes and normal physiological processes. The proteins cadherin 2 and MMP2 are substrates of this protease. MMP16 is an important paralog of this gene.
In the present study, we comprehensively assessed the expression and prognostic value of 26 MMPs in UVM. In our study, MMP24 was not found to be upregulated in UVM and the expression of MMP24 was not associated with overall survival and shorter disease-free survival in uveal melanoma patients. However, MMP24 play a significant role in the progression from stage 3 to stage 4 for UVM patients.
To date, our research is the first to explore the association between UVM and the matrix metalloproteinase family. However, there are some limitations in our study. First, due to the limitation of conditions, there is no relevant experimental verification in our study. At the appropriate time in the future, we will carry out related experiments. Second, due to the lack of clinical data on UVM in relevant databases, such as TCGA, we could not find sufficient data for an effective analysis.