Deregulated matriptase activity in oral squamous cell carcinoma promotes the infiltration of cancer-associated fibroblasts by paracrine activation of protease-activated receptor 2.
Cancer-associated fibroblasts (CAFs) are known to contribute to cancer progression. We have reported that cell surface expression of hepatocyte growth factor activator inhibitor 1 (HAI-1) is decreased in invasive oral squamous cell carcinoma (OSCC) cells. This study examined if HAI-1-insufficiency contributes to CAF recruitment in OSCC. Serum-free conditioned medium (SFCM) from a human OSCC line (SAS) stimulated the migration of 3 human fibroblast cell lines, NB1RGB, MRC5 and KD. SFCM from HAI-1-knockdown SAS showed an additive effect on the migration of NB1RGB and MRC5, but not KD. SAS SFCM induced protease-activated receptor-2 (PAR-2) expression in NB1RGB and MRC5, but not in KD, and a PAR-2 antagonist blocked the stimulatory effect of HAI-1 knockdown on migration of the PAR-2 expressing cell lines. Moreover, HAI-1-deficient SFCM showed additive stimulatory effects on the migration of wild-type but not PAR-2-deficient mouse fibroblasts. Therefore, the enhanced migration induced by HAI-1-insufficiency was mediated by PAR-2 activation in fibroblasts. This activation resulted from the deregulation of the activity of matriptase, a PAR-2 agonist protease. HAI-1 may thus prevent CAF recruitment to OSCC by controlling matriptase activity. When HAI-1 expression is reduced on OSCC, matriptase may contribute to CAF accumulation by paracrine activation of fibroblast PAR-2. Immunohistochemical analysis of resected OSCC revealed increased PAR2-positive CAFs in 35% (33/95) of the cases studied. The increased PAR-2 positive CAFs tended to correlate with infiltrative histology of the invasion front and shorter disease-free survival of the patients.
Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan.
Ai
A
Kanemaru
Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan.
Koji
K
Yamamoto
Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan.
Makiko
M
Kawaguchi
Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan.
Tsuyoshi
T
Fukushima
School of Medicine, Lambardi Comprehensive Cancer Centre, Georgetown University, Washington, DC.
Chen-Yong
CY
Lin
School of Medicine, Lambardi Comprehensive Cancer Centre, Georgetown University, Washington, DC.
Michael D
MD
Johnson
INSERM U970, Paris Cardiovascular Research Centre, Paris, France.
Eric
E
Camerer
Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan.
Hiroaki
H
Kataoka
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000072645:Cancer-Associated Fibroblasts / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics*; D044464:Receptor, PAR-2 / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*
D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D008565:Membrane Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D044464:Receptor, PAR-2; C109149:SPINT1 protein, human; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human
HAI-1; cancer-associated fibroblasts; matriptase; oral squamous cell carcinoma; protease-activated receptor 2