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Tissue Factor Pathway Inhibitor 2 (TFPI-2) is a Kunitz-type serine protease inhibitor that plays a crucial role in modulating the extracellular matrix (ECM) and inhibiting various proteases. It is a structural homolog of Tissue Factor Pathway Inhibitor (TFPI) but exhibits distinct biological functions. TFPI-2 is synthesized and secreted by various cell types, including endothelial cells, smooth muscle cells, fibroblasts, keratinocytes, and urothelium .
TFPI-2 belongs to the superfamily of serine protease inhibitors containing one or more Kunitz-type domains. The human TFPI-2 gene is located on chromosome 7 (7q22 region) and consists of five exons and four introns . The mature TFPI-2 protein has a short acidic N-terminal region, three tandem Kunitz inhibitor domains, and a C-terminal basic region. Depending on the nature of glycosylation, TFPI-2 presents in three forms: 27 kDa, 31 kDa, and 33 kDa .
The N-terminal Kunitz domain 1 of TFPI-2 exhibits inhibitory activity on serine proteases, while the two domains of TFPI-1 downstream of the Kunitz domain exert inhibitory effects on FVIIa/TF and FXa, respectively . TFPI-2 readily inhibits trypsin, plasmin, chymotrypsin, cathepsin G, plasma kallikrein, and the factor VIIa-tissue factor complex .
TFPI-2 plays a pivotal role in regulating ECM remodeling, a process essential for tumor invasion and metastasis . It inhibits the trypsin- and plasmin-mediated activation of promatrix metalloproteinases proMMP-1 and proMMP-3 and suppresses the production of active MMP-2 . Additionally, TFPI-2 is up-regulated in human atherosclerotic coronary arteries compared to normal, healthy arteries .
TFPI-2 has been reported to be an epigenetically silenced tumor suppressor and an independent prognostic factor in various human cancers . Elevated serum levels of TFPI-2 have been observed in ovarian and endometrial cancers, with increased levels correlating with poor prognosis in endometrial cancer . This paradoxical pro-invasive effect in certain cancers raises questions about the role of TFPI-2 in cancer progression and its potential as a therapeutic target.