Overexpression of human beta-defensin-3 in oral dysplasia: potential role in macrophage trafficking.
Human beta-defensins (hBDs) are small, cationic antimicrobial peptides produced by oral and other mucosal epithelia. More recently, hBDs have been shown to regulate adaptive immunity. In this study, we provide new information about the potential role of hBD-3 in the progression of oral cancer. In normal human oral epithelia, hBD-3 is produced by mitotically active cells in the basal layers of oral epithelium, whereas hBD-1 and -2 are coexpressed in the differentiated spinosum and granulosum layers. Interestingly, premalignant cells in carcinoma in situ lesions overexpress hBD-3, but not hBD-1 and hBD-2, correlating with specific recruitment and infiltration of macrophages. Our in vitro studies demonstrate that hBD-3 chemoattracts THP-1 monocytic cells and that epidermal growth factor (EGF) significantly induces hBD-3 expression in oral epithelial cells via mitogen-activated protein kinase (MAPK) kinase MEK1/2, p38 MAPK, protein kinase C (PKC), and phosphoinositide 3 kinase (PI3K), but not via Janus kinase (JAK) and signal transducer and activator of transcription (STATs). These results suggest that hBD-3 serves as a mitogen responsive gene in the initiation of oral cancer and may act as a motility signal to recruit tumor-associated macrophages.
Kawsar
Hameem I
HI
Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Weinberg
Aaron
A
Hirsch
Stanley A
SA
Venizelos
Andrea
A
Howell
Scott
S
Jiang
Bin
B
Jin
Ge
G
D002278:Carcinoma in Situ / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008856:Microscopy, Fluorescence; D009062:Mouth Neoplasms / Q000378:metabolism*; D010770:Phosphotransferases / Q000494:pharmacology; D011230:Precancerous Conditions / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000494:pharmacology; D023083:beta-Defensins / Q000096:biosynthesis* / Q000378:metabolism
C406407:DEFB1 protein, human; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D050791:STAT Transcription Factors; D023083:beta-Defensins; D004815:Epidermal Growth Factor; D010770:Phosphotransferases