The Mechanism And Clinical Research Of TFPI-2 Inhibiting Proliferation And Invasion Of Breast Cancer

Objective: Breast cancer has become the most common cancer in women worldwide,which seriously threatens the life and health of women.With early lesions and systemic treatment,overall survival of breast cancer has increased considerably,while aggressive metastasis was a major cause of death in patients with metastatic breast cancer.TFPI-2 has been identified as an important tumor suppressor gene,which inhibits tumor cell proliferation,migration,and invasion,leading to the inhibition of tumor development by inhibiting matriptase activity and regulating the expression of some genes.Therefore,in this study,we investigated the molecular mechanism by which TFPI-2 inhibits breast cancer proliferation and invasion and its clinical significance.Methods: The data of breast cancer in TCGA database were downloaded,the expression profile of TFPI-2 gene and related clinical information were collated,and the expression level of TFPI-2 in breast cancer and its relationship with clinicopathologic features and its impact on prognosis were studied.RNA-seq was also used to analyze the changes in breast cancer gene expression profiles after TFPI-2 overexpression,and the down-regulated differential genes were subjected to GO and KEGG analysis.RNA-seq and Ch IP-seq data were then integrated and screened for TFPI-2 potential target genes in breast cancer,and target genes were picked for validation using Ch IP-q PCR and luciferase reporter.Results: The TCGA database revealed that TFPI-2 was significantly downregulated in BRCA tissues,and the low expression was significantly negatively associated with the overall survival of the patients.Univariate Cox regression analysis revealed that the age and M stage were significant independent prognostic factors.RNA sequencing(RNA-seq)identified over5000 differentially expressed genes(DEGs).Gene ontology and KEGG pathway analysis shown that the DEGs were associated with cell cycle,cell differentiation,proteoglycans in cancer and pathways associated with cancer.Analysis combining of RNA-seq and Ch IP-seq data,we identified 74 genes as regulated target genes of TFPI-2 in the MDA231 cells.Among them,melanocyte inducing transcription factor(MITF)gene expression was repressed by TFPI-2,which was further verified by a luciferase reporter assay and Ch IP-q PCR.Conclusions: TFPI-2 was low expressed in breast cancer and that its expression was associated with poor prognosis of breast cancer patients.Furthermore,suppression of TFPI-2 inhibits the occurrence and progression of breast cancer by regulating MITF expression.So TFPI-2 may serve as a potential therapeutic targets for BC.