Abstract
TFPI-2 has recently been recognized as a tumor suppressor, which not only plays a fundamental role in modulation of ECM integrity, but also involves the regulation of many oncogenes. In this study, we investigated the potential mechanism of TFPI-2 in the suppression of breast cancer growth and invasion. We showed that, with either over-expression of TFPI-2 or after treatment with exogenous rTFPI-2, breast cancer cells exhibited reduced proliferation and invasion. We demonstrated that in addition to being secreted, TFPI-2 was also distributed throughout the cytoplasm and nucleus. Nuclear localization of TFPI-2 contributed to inhibition of MMP-2 mRNA expression, which could be reversed after the nuclear localization signal was deleted. In the nucleus, interaction of TFPI-2 with Ap-2α attenuated the binding of AP-2α to the MMP-2 promoter, therefore reducing the transcriptional activity of the gene. Our results suggest that one of the mechanisms by which TFPI-2 inhibits breast cancer cell invasion could be via the regulation of MMP-2 gene transcription.
Highlights
TFPI-2 is expressed and secreted into the extracellular matrix (ECM) of various types of human tissues, such as the liver, skeletal, muscle and pancreas[1,2,3]
Transwell assays showed that cell invasion was markedly decreased in MDA231/TFPI-2 cells, and was increased in MDA231/Sh2 cells compared to control and parental cells
TFPI-2 is a member of the Kunitz-type serine proteinase inhibitor family and has been shown to protect the extracellular matrix from degradation, thereby inhibiting tumor cell invasion and metastasis[4,9,24]
Summary
TFPI-2 is expressed and secreted into the extracellular matrix (ECM) of various types of human tissues, such as the liver, skeletal, muscle and pancreas[1,2,3]. Secretion of TFPI-2 into the ECM inhibits plasmin-mediated activation of MMPs and maintains the integrity of the ECM, repressing tumor cell invasion[4,5]. In the cytoplasm of HT1080 fibrosarcoma cells, TFPI-2 interacted with prosaposin to inhibit its invasion-promoting effects[17]. We investigated the mechanisms underlying the invasion-suppressive effect of TFPI-2 in breast cancer cells. With over-expression of TFPI-2 or after treatment with exogenous rTFPI-2, we demonstrated that breast cancer cells exhibited a reduced ability to invade. Interaction of the two proteins attenuated the binding ability of AP-2α to the promoter of the MMP-2 gene, thereby reducing its transcriptional activity. Which suggests that one of the mechanisms that TFPI-2 suppresses migration and invasion of breast cancer cells could be mediated by the regulation of MMP-2 expression
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