The prognostic and diagnostic value of tissue inhibitor of metalloproteinases gene family and potential function in gastric cancer.

Abstract

Background: Tissue inhibitor of metalloproteinases (TIMP) gene family, including TIMP1, TIMP2, TIMP3 and TIMP4, was found to be correlated with serval cancers. Still the diagnostic and prognostic study of it in gastric cancer (GC) have few reports.Methods and materials: In this study, the gene expression and clinical data were acquired from the Cancer Gene Atlas (TCGA), function enrichment was used by several databases for verifying known function. Operating characteristic (ROC) curves with area under the curve (AUC) used to assess diagnostic value. Survival analysis and joint-effects survival analysis was performed by the Kaplan-Meier curve. The results were adjusted by cox-regression model. Nomogram is used to directly predict the survival rate for individual GC patient. The potential mechanism for diagnostic and prognostic value was assessed by gene set enrichment analysis (GSEA). Further functions of gene were verified by cell proliferation, migration and invasion assays in human gastric cancer cell line.Results: TIMP1 was expressed in GC tissue was higher than normal gastric tissue. TIMP3 and TIMP4 have expressed in normal gastric tissue were higher than GC tissue. TIMP1, TIMP3 and TIMP4 have potential diagnostic value (AUC=0.842, 0.729, 0.786 respectively; all P<0.01). Low expression of TIMP2 and TIMP3 associated with favorable overall survival (all P<0.05). TIMP2 and TIMP3, which had significantly affection of prognosis were found having some function such as tRNA processing, cell cycle pathway ncRNA processing. The silencing of TIMP3 could inhibit the migration and invasion of gastric cancer cell.Conclusion: We analyzed the TIMP gene family in GC, and the prognostic and diagnostic value. TIMP1 and TIMP2 could be used as diagnostic biomarkers in GC. TIMP2 and TIMP3 could be used as potential biomarkers for GC's prognosis.