Cyclin D1 overexpression increases susceptibility to 4-nitroquinoline-1-oxide-induced dysplasia and neoplasia in murine squamous oral epithelium.
The cyclin D1 oncogene is frequently amplified/overexpressed in oral squamous cell carcinomas. Mice with overexpression of cyclin D1 targeted to the stratified squamous epithelia of the tongue, esophagus, and forestomach develop a phenotype of epithelial dysplasia at these sites. In this study, we examined the effect of cyclin D1 overexpression on susceptibility of mice to carcinogen-induced tumorigenesis, using 4-nitroquinoline-1-oxide (4NQO), an established potent oral carcinogen in mice. Cyclin D1 overexpressing mice and nontransgenic littermates were administered 4NQO (20 or 50 parts per million (ppm) in the drinking water) for 8 wk and monitored for an additional 16 wk. Histopathological analyses of the tongue revealed significantly higher severity of dysplasia in the cyclin D1 overexpression mice, compared with nontransgenic controls and with untreated controls. Moreover, only the cyclin D1 overexpression mice developed neoplastic lesions in the oro-esophageal epithelia. Examination of the dysplastic and neoplastic lesions revealed abnormal proliferation. Our findings suggest that cyclin D1 overexpression enhances susceptibility to carcinogen-induced oral tumorigenesis. These results underscore the importance of cyclin D1 in the process of oral neoplastic development. Further, they emphasize the value of this transgenic model to study the pathogenesis of oral precancer and cancer and establish it as a model system to test candidate agents for chemoprevention of upper aero-digestive cancer.
Wilkey
Jonathan F
JF
Section of Oral & Maxillofacial Radiology, University of Connecticut School of Dental Medicine, Farmington, Connecticut 06030, USA.
Buchberger
Glenn
G
Saucier
Kirsten
K
Patel
Salony M
SM
Eisenberg
Ellen
E
Nakagawa
Hiroshi
H
Michaylira
Carmen Z
CZ
Rustgi
Anil K
AK
Mallya
Sanjay M
SM
D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D000818:Animals; D015152:Blotting, Northern; D002273:Carcinogens / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004195:Disease Models, Animal; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D053555:Keratin-5 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009061:Mouth Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics
D002273:Carcinogens; D019941:Cyclin-Dependent Kinase Inhibitor p16; D053555:Keratin-5; D019394:Ki-67 Antigen; D019938:Cyclin D1; D015112:4-Nitroquinoline-1-oxide