title: Loss of membrane-bound serine protease inhibitor HAI-1 induces oral squamous cell carcinoma cells' invasiveness.
abstract: A loss of balance between cell membrane-associated proteases and their inhibitors may underlie cancer invasion and metastasis. We analysed 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 the growth of both lines in vitro but significantly enhanced SAS tumourigenicity in vivo, which was accompanied by histological changes suggestive of the epithelial-mesenchymal transition. Both HAI-1-KD lines 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 the expression of CD24, S100A4, CCND2 and DUSP6, all of which are involved in tumour 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.
authors.affiliation: Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Baba
authors.forename: Makiko
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukushima
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Orikawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Yorita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Chen-Yong
authors.initials: CY
authors.lastname: Lin
authors.forename: Sumio
authors.initials: S
authors.lastname: Sakoda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D053491:Proteinase Inhibitory Proteins, Secretory / Q000172:deficiency*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
chemical_list: D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; D012697:Serine Endopeptidases; C485595:matriptase