Publication Date:
2012-04-17
Description:
A loss of balance between cell membrane-associated proteases and their inhibitors may underlie cancer invasion and metastasis. We analyzed the roles of a membrane- associated serine protease inhibitor, HAI-1, in oral squamous cell carcinoma (OSCC). While membranous HAI-1 was widely observed in cancer cells of human OSCC tissues, this was significantly reduced at the infiltrative invasion front. In vitro , HAI-1 was detected in all eight OSCC cell lines examined, in which its cognate membrane protease, matriptase was also expressed. HAI-1 expression knock down (KD) in OSCC lines, SAS and HSC-3, reduced growth of both lines in vitro , but significantly enhanced SAS tumorigenicity in vivo , which was accompanied by histological changes suggestive of the epithelial to mesenchymal transition. Both HAI-1-KD lnes also exhibited significantly enhanced migratory capability, and membrane-associated but not truncated HAI-1 was required to rescue this phenotype. Other OSCC lines (HSC-2, Sa3, Ca9-22) also showed enhanced migration in response to HAI-1 KD. The enhanced migration is partly attributed to dysregulation of matriptase as simultaneous matriptase KD alleviated the migration of HAI-1-KD cells. HAI-1 deficiency also altered expression of CD24 , S100A4 , CCND2 and DUSP6 , all of which are involved in tumor progression. While matriptase was involved in the increased CD24 expression associated with HAI-1 deficiency, the protease appeared to be not responsible for the altered expression of other genes. Therefore, a matriptase-independent mechanism for the invasiveness associated with HAI-1 KD is also present. Together, these observations suggest that HAI-1 has a crucial suppressive role in OSCC cell invasiveness. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Print ISSN:
0022-3417
Electronic ISSN:
1096-9896
Topics:
Medicine
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