The Expression Of TIMP-4 And MMP-2 In Gastric Cancer And Their Clinical Significances

Background: Globally,gastric cancer(GC),a malignant tumor originating in the Gastric mucosa,ranks fififth in prevalence and third in fatalities,and shows high rate of rise in morbidity.Gastric cancer is one of the major cancers leading to human death,which seriously endangers human health.Therefore,the timely treatment and prognosis judgment of gastric cancer are very important.At present,the prognosis of gastric cancer is relatively poor,and the 5-year survival rate is less than 30%,partly because of the rapid invasion and metastasis of tumor cells,and the dysregulation of cell metastasis-related genes(MMPs,TIMPs,nm23,etc.)are closely related to the occurrence and development of tumors.Extracellular matrix(ECM)accumulation is an important factor in malignant tumor invasion and metastasis.ECM is regulated by proteolytic enzymes such as matrix metalloproteinases(MMPs)and their endogenous inhibitors TIMPs.Metalloproteinase tissue inhibitor-4(TIMP-4)is a protein that inhibits the activity of metalloproteinases and regulates the activity of matrix metalloproteinases.Metalloproteinase-2(MMP-2)participated in the extracellular matrix and basement membrane degradation of collagen type ?.Studies have shown that the expression of TIMP-4 and MMP-2 is associated with the prognosis,stage and disease progression of glioma.However,the expression of these two markers in gastric cancer and their relationship with the prognosis of patients have not been reported at home and abroad.In this study,immunohistochemistry and real-time fluorescence PCR were used to investigate the expression of TIMP-4 and MMP-2 in gastric cancer from the protein and gene levels,and the correlation between the two was analyzed to provide theoretical basis for studying the occurrence and development mechanism of GC.Objective: To analyze the expression of tissue inhibitor of metalloproteinase-4(TIMP-4)and matrix metalloproteinase-2(MMP-2)in gastric cancer(GC)and adjacent tissues,and to explore their clinical significance in gastric cancer.Methods: The expression levels of TIMP-4 protein and MMP-2 protein in 75 gastric cancer tissues and 42 adjacent tissues were analyzed by immunohistochemistry.Real-time fluorescence PCR(RT-q PCR)and Western Blot were used to detect the expression levels of TIMP-4 and MMP-2 in 23 pairs of surgically excised fresh gastric cancer tissues and adjacent tissues.At the same time,Pearson correlation analysis was used to analyze the relationship between TIMP-4/MMP-2 and GC clinicopathological parameters that explore the correlation between their expressions.Finally,Kaplan-meier survival analysis of gastric Cancer in TCGA(The Cancer Genome Atlas)was performed to analyze The correlation between high TIMP-4 and MMP-2 expression in gastric Cancer and overall survival.Results:1.In 75 cases of GC tissues,the positive expression rate of TIMP-4 protein was 86.67%,and the positive expression rate of MMP-2 protein was 90.67%.The positive expression rate of TIMP-4 was 22 cases(52.3%),and the positive expression rate of MMP-2 was 23cases(54.7%).The differences were statistically significant compared with adjacent tissues(P<0.01).The expression of MMP-2 protein in GC tissues was closely correlated with lymph node metastasis(P<0.01),and was statistically correlated with gastric cancer staging(P<0.05).However,there was no significant difference with gender,age, tumor size and degree of differentiation.2.There was no statistical correlation between the expression of TIMP-4 protein in GC tissues and gender,age,tumor size,lymph node metastasis,tumor differentiation degree and stage(P> 0.05).The relative expression level of TIMP-4 m RNA in GC tissues was2.240±0.728,and that in para-cancer tissues was 1.691±0.772,showing no significant difference between the two groups(t=2.006,P>0.05).3.The relative expression level of MMP-2 m RNA in GC tissues was 1.718±0.921,and that in paracancer tissues was 1.110±0.845.The expression level in gastric cancer tissues was higher than that in paracancer tissues and the difference was statistically significant(t=2.123,P<0.05).4.The relative expression level of TIMP-4 protein in GC tissues was 0.693±0.117,and that in para-cancer tissues was 0.361±0.103.The expression level in gastric cancer tissues was higher than that in paracancer tissues and the difference was statistically significant(t=5.114,P<0.05).The relative expression level of MMP-2 protein in GC tissues was 0.682±0.198,and that in paracancer tissues was 0.371±0.136.The expression level in gastric cancer tissues was higher than that in paracancer tissues and the difference was statistically significant(t=7.198,P<0.05).5.Pearson correlation analysis revealed a significant positive correlation between TIMP-4 protein and MMP-2 protein expression in GC tissues(r=0.351,P<0.01).6.Kaplan-meier survival analysis showed that gastric cancer patients with high expression of TIMP-4 and MMP-2 had a poor prognosis.Conclusion: TIMP-4 and MMP-2 proteins are highly expressed in gastric cancer tissues,suggesting that patients with gastric cancer have a poor prognosis and may be involved in the occurrence and development of gastric cancer,which is expected to be a potential biomarker for predicting gastric cancer metastasis.