Abstract
TFPI-2 has been recognized as a potent tumor suppressor gene. Low expression of TFPI-2 results in enhanced growth and metastasis of a variety of human tumors. In the present study, we investigated the mechanism responsible for the tumor suppressive effect of TFPI-2. Overexpression of TFPI-2 decreased phosphorylation of ERK1/2 and the translocation of p-ERK1/2 from cytoplasm into the nucleus, and eventually resulted in a reduced cell proliferation. Immunoprecipitation assays identified myosin-9 and actinin-4 as TFPI-2-interacting proteins. Full-length TFPI-2 was required for binding to actinin-4, whereas the N + KD1 regions of TFPI-2 were sufficient to interact with myosin-9. Although overexpression of TFPI-2 or TFPI-2/N + KD1 does not affect the expression of actinin-4 and myosin-9, it inhibits the migration and invasion of human breast cancer cells. Our results suggest that TFPI-2 suppresses cancer cell proliferation and invasion partly through the regulation of the ERK1/2 signaling and through interactions with myosin-9 and actinin-4.
Highlights
Breast cancer metastasis is one of the leading causes of cancer-related mortality in women worldwide and is the main reason for treatment failure[1,2]
TFPI-2 is widely expressed in various human tissue cells, such as liver, skeletal, muscle, heart, kidney and pancreas, where the protein is secreted into the extracellular matrix (ECM) to prevent ECM hydrolysis through inhibiting plasmin-mediated activation of MMPs8,9
We show that overexpression of TFPI-2 results in reduced cell proliferation, which is accompanied by reduced phosphorylation of EGFR/ERK1/2 and decreased translocation of pERK1/2 into the nucleus
Summary
Breast cancer metastasis is one of the leading causes of cancer-related mortality in women worldwide and is the main reason for treatment failure[1,2]. TFPI-2 is able to translocate into the nucleus and suppress the expression of MMP-2 mRNA through the interaction with AP-2a, a transcription factor involved in expression of several genes[13]. These studies suggest that in addition to prevention of the proteolytic degradation of the extracellular matrix, TFPI-2 can function to suppress cancer cell invasion through the regulation of its binding partners within the cytoplasm and the nucleus. Our results suggest that TFPI-2 represses cell proliferation through regulation of ERK signaling and that the interactions of TFPI-2 with actinin-4 and myosin-9 contribute to the suppressive effect of TFPI-2 on cell invasion
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