Plasminogen activator inhibitor-1 (PAI-1) modifies the formation of aggressive fibromatosis (desmoid tumor)
Oncogene(2005)
摘要
Aggressive fibromatosis is a mesenchymal neoplasm associated with mutations, resulting in β -catenin-mediated transcriptional activation. We found that plasminogen activator inhibitor-1 ( PAI-1 ) was upregulated fourfold in aggressive fibromatosis. We investigated the ability of β -catenin to regulate a PAI-1 reporter, and found that PAI-1 is an indirect target. To determine the role of PAI-1 in vivo , a mouse containing a targeted deletion in Pai-1 was crossed with a mouse that develops aggressive fibromatosis and gastrointestinal tumors ( Apc/Apc 1638N mouse). Pai-1 deficiency reduced the number of aggressive fibromatosis tumors formed, but not the number of gastrointestinal tumors. Deficiency of Pai-1 reduced tumor cell proliferation and motility rate. Although PAI-1 can alter cell motility by competing for a common binding site on vitronectin, blocking this site did not alter the motility rate. The number of cells moving through matrigel (invasion rate) did not change with Pai-1 deficiency, but because of the low motility rate the invasion index (invasion rate/motility) was increased in Pai-1 -deficient cells. This suggests a proteolytic effect for PAI-1 regulating cell invasiveness. Our study found that, although PAI-1 has cellular effects that could inhibit or enhance tumor growth, on balance, it acts as a tumor enhancer in aggressive fibromatosis.
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关键词
aggressive fibromatosis,plasminogen activator inhibitor-1,β-catenin,transgenic mice,adenomatous polyposis coli,cell proliferation,cell motility
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