Difference analysis of expression of MMP14 in pan-cancer tissues and normal tissues
In order to analyze the expression level of MMP14 mRNA in normal tissues and tumors, we analyzed relevant data from Oncomine and Timer databases. In the Oncomine database, compared to normal tissue, The results showed that the expression of MMP14 was higher in the Brain and CNS (central nervous system) Cancer, Breast Cancer, Colorectal Carcinoma, Esophageal Cancer, Head and Neck Cancer, Kidney Cancer, Lung Cancer, Melanoma, Ovarian Cancer, Pancreatic Cancer, and Sarcoma (Figure 1a).On the other hand, MMP14 expression was decreased only in the Liver Cancer.
At the same time, we further confirmed the expression of MMP14 in various cancers compared to normal tissues using the TIMER database (Figure 1b).The results showed that the BLCA(Bladder Cancer), BRCA(Breast Cancer), CHOL(Cholangio carcinoma),COAD(Colon adenocarcinoma),ESCA (carcinoma), KIRC (Kidney renal clear cell carcinoma), KIRP (Kidney renal papillary cell carcinoma), LIHC (Liver hepatocellular carcinoma),LUAD( Lung adenocarcinoma), LUSC (Lung squamous cell carcinoma), READ (Rectum adenocarcinoma), STAD (Stomach adenocarcinoma) and THCA (Thyroid carcinoma) tissues were significantly increased compared to the normal tissues. Tumors with reduced MMP14 expression compared to normal tissue included: HNSC (Head and Neck squamous cell carcinoma), KICH (Kidney Chromophobe), PRAD (Prostate adenocarcinoma), UCEC(Uterine Corpus Endometrial Carcinoma).
Prognostic role of MMP14 in different tumors
In order to investigate the prognostic effect of MMP14 on different tumors, we analyzed data from different databases. First, the overall survival(OS), disease-special survival(DSS), disease-free survival(DFS), disease-free interval(DFI) of MMP14 were analyzed by univariate Cox proportional risk regression model in the TCGA database.KM(Kaplan-Meier Plotter) survival curves were accordingly plotted for tumors with significant prognosis (Figure 2).
First, we used gene expression profile data to analyze the relationship between MMP14 expression and tumor prognosis in 33 tumors in the TCGA database.Univariate survival analysis resulted in the forest plot of prognosis for 33 tumors, as shown in Figure 2a. KM plot 2b was also plotted with a significant correlation with MMP14 expression. Can see MMP14 low expression in the ACC, BLCA, GBM, HNSC, KIRC, LGG, LIHC, LUAD, MESO, OV, PAAD, and overall survival in THCA positively related to prognosis.
Because of the statistical data of the tumor death, so we use the TCGA database analysis of 33 kinds of tumor disease specific survival (DSS), get the forest figure and significantly associated with relationship of KM, the result is shown in figure 3, from figure 3 we can find out factors other than the tumor death, lower expression of MMP14 positively related to the prognosis of tumor types with ACC, PAAD, UCEC.
Considering the influence of disease factors on survival analysis results, DFS (disease-free survival) : disease-free survival, which is used to evaluate radical surgery, is generally used to indicate the time from treatment to recurrence.We performed DFS analysis on the above data and obtained the forest map and the KM map with significant prognosis, as shown in Figure 4.It can be seen after radical surgery, the lower expression of MMP14 has significant effects on prognosis of tumor have the ACC, BLCA, BRCA, GBM, KRIC, LGG, LIHC, MESO, OV, PAAD, YHCA, UVM.
PFS is an indicator of how well cancer is treated after palliative care.We also analyzed the PFS, the results data (figure 5), can know from figure 5, after palliative therapy, the lower expression of prognosis of MMP14 effects obvious tumor BLCA, BRCA, KICH, KIRC, LGG, LUSC.
Relationship between expression of MMP14 and immune infiltration in diffuse tumors
We obtained score data of 6 immunoinfiltrating cells in 33 tumors from the TIMER database.Then the expression of MMP14 was correlated with 6 species (B_cells, CD4_tcells, CD8_t cells, macrophages, dendritic Cells, and Neutrophils), and the correlation between the scores of immune cells was analyzed (Supplement 1,2,3,4). We found that the expression of MMP14 was most significantly associated with the infiltration of immune cells in the 3 tumors: BLCA, BRCA, and COAD (Figure 6).
Immune cells and stromal cells in tumor microenvironment is two main cell types, we was analyzed by using the R package Estimate each tumor samples immune score and score matrix, it is concluded that 33 MMP14 expression in tumor and immune score (Immunescore) relationship, it can be seen in the correlation was statistically significant (P < 0.05), the expression of MMP14 and immune score was positively related to: BLCA, BRCA, from cesg, COAD, DLBC, ESCA, GBM, HNSC,KICH,KIRP, LGG, LIHC, LUAD, LUSC, OV,PAAD,PCPG,PRAD,READ,STAD, THCA. At the same time, ACC, SKCM, TGCT and THYM were negatively correlated (Figure 7).In the relationship between the expression of MMP14 of Stromalscore, the expression of MMP14 was positively correlated with the expression of immune matrix under the condition of statistical significance (P < 0.05) :BLCA, BRCA, CESC, COAD, DLBC, ESCA, GBM,HNSC, KICH,KIRC, KIRP, LAML, LGG, LIHC, LUAD, LUSC, MESO, OV, PAAD, PCPG, PARD, READ, SARC, STAD TGTC, THCA, THYM, USEC,UCS, UVM. Negative correlation was found in SKCM (P=0.24) (Fig. 8).The three tumors with the most significant correlation between MMP14 expression and immune cell score are Stromalscore: BRCA,CESC, and COAD(Figure 9A); Immunescore: COAD; LGG; PCPG (figure 9 b).In conclusion, it can be seen that the expression of MMP14 is associated with immune infiltration.
The expression of MMP14 is associated with immune checkpoint genes in endemic cancer
From the above results, it can be seen that the expression of MMP14 is correlated with the level of immune infiltration, so we further studied the relationship between MMP14 and 47 common immune checkpoint genes (Figure 10).The results showed that the expression of MMP14 was associated with 41 immune checkpoint genes in PRAD, 36 in LGG, 33 in THCA and 29 in KICK.We also found that the immune checkpoint gene CD276 was significantly associated with MMP14 expression in 28 of 33 tumors.The expression of MMP14 is associated with immune checkpoint genes in endemic cancer, and these results provide further evidence that MMP14 expression is associated with the level of immune invasion.
The expression of MMP14 is associated with gene mismatch repair (MMR) and DNA methylation levels in endemic cancer
MMR is an important correction factor for base mismatches, base deletions and insertion errors during DNA replication and recombination, and plays an important role in maintaining gene stability (25).MMR genes play a crucial role in maintaining the stability of MMR genes. Deletions of some important MMR genes will lead to major errors in DNA replication and recombination, leading to the occurrence of tumors (26).So, in order to study the expression of MMP14 on the influence of the cancer process, we choose for the MMR of several important genes and expression level of MMP14 this direction, the influence of the results (figure 11. A), we can see from the picture the expression of MMP14 and MMR genes larger tumors have a KICK, correlation KIRC, LGG, LIHC, LUSC, OV, PAAD, STAD, TGCT, THCA, UCEC, is one of the most relevant LGG, UCEC.
A growing number of recent studies have shown that DNA methylation plays a role in the progression of numerous tumors (27,28).Therefore, in this study, we evaluated the relationship between four DNA methyltransferases and MMP14, as shown in Figure 11. It can be seen that the expression of MMP14 is highly correlated with four DNA methyltransferases in many tumors, especially SARC, SKCM, STAD, TGCT, UCEC, BRCA, HNSC, KICH, Kirc, LGG, LIHC, MESO, OV, and PAAD.These data suggest that MMP14 can affect the occurrence and progression of many tumors through DNA mismatch repair and DNA methylation.
Relationship between MMP14 expression and tumor mutation load (TMB) and microsatellite instability (MSI) in endemic cancer
Recently it has been reported that tumor mutation load (TMB) plays an important role as a biomarker in predicting the response to immune checkpoint inhibitors (ICIs) (29,30,31), such as PD-1/PD-L1.Microsatellite instability (MSI), which also occurs in the vast majority of tumors, may also serve as a novel and important biomarker to predict the effects of immune checkpoint inhibitors (32,33), as well as PD-1.In this study, we investigated the relationship between MMP14 and tumor mutation load (TMB) and microsatellite instability (MSI) in endemic cancer.The analysis results showed that the expression of MMP14 was positively related with TMB: THYM, SKCM, SARC, SARC PAAD, LUAD, LGG.In contrast, tumors in which MMP14 expression was negatively correlated with TMB included BLCA,HNSC,LIHC, and PRAD(Figure 12A).In terms of MSI, MMP14 expression was positively correlated with MSI in the following tumors: TGCT,SARC and COAD;The tumors in which MMP14 expression was negatively correlated with MSI included UCEC, PRAD (Figure 12B).