Proliferation and differentiation markers in snuff-induced oral mucosal lesions.
BACKGROUND
Regular use of snuff is known to cause whitish oral mucosal lesions of variable severity at the usual quid placement site. The main aim of this study was to elucidate cellular mechanisms involved in snuff-induced epithelial changes.


METHODS
Expression patterns for markers of cell proliferation (PCNA, Ki-67), cell cycle regulation (p53, p21), keratin changes (pankeratin, CK18, CK19), cell stress (HSP 70) and collagen type IV in 14 snuff-induced oral mucosal lesions and 12 control samples were analyzed by immunohistochemistry (IHC).


RESULTS
On light microscopy, all snuff-induced lesions were characterized by a hyperkeratinized and thickened epithelium. Some vacuolized cells, markers of cell degeneration, were frequently seen (in 9/14 of the samples) in the superficial layers in epithelia. Expression of PCNA and Ki-67 was found in a statistically significantly fewer cells in snuff-induced lesions (P < 0.001) than in the controls. This indicates that epithelia in snuff-induced lesions are not thickened as a result of increased cellular proliferation, but by protracted turnover of differentiating cells. Of cell cycle markers, p21 was found be up-regulated in 4/14 snuff-induced lesions, probably by p53-independent pathways. Only two snuff-induced lesions showed p53 positivity. However, the number of stained cells with p53 and p21 was not statistically different from that in controls. Expression of CK18, but not any alterations in CK19 expression, was seen in 5 of 14 snuff-induced lesions. Snuff also seems to stimulate the expression of collagen type IV, possibly by basal cells, as indicated by the thickened staining of the basal lamina.


CONCLUSIONS
The findings of this study showing suppressed cellular proliferation and infrequent p53 dysfunction in snuff lesions may partly explain why dysplastic changes are seldom seen in mucosal lesions induced by the Scandinavian type of snuff.
Department of Oral Pathology and Radiology, Institute of Dentistry and MediCity Research Laboratory, Faculty of Medicine, University of Turku, Finland. Student Health Service, Turku, Finland. marina.merne@turku.fi
Marina
M
Merne
Ilkka
I
Heinaro
Hannu
H
Lähteenoja
Stina
S
Syrjänen
D000293:Adolescent; D000328:Adult; D000368:Aged; D001485:Basement Membrane / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation; D002455:Cell Division; D024141:Collagen Type IV / Q000032:analysis; D004396:Coloring Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000032:analysis / Q000378:metabolism; D004848:Epithelium / Q000473:pathology; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D008046:Lip / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009059:Mouth Diseases / Q000209:etiology / Q000473:pathology*; D009061:Mouth Mucosa / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D013223:Statistics as Topic; D014030:Tobacco, Smokeless / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D015854:Up-Regulation; D014617:Vacuoles / Q000648:ultrastructure
D015415:Biomarkers; C493956:CDKN1A protein, human; D024141:Collagen Type IV; D004396:Coloring Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D007633:Keratins