title: High frequency methylation of p16INK4A gene during 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis.
abstract: The p16INK4A tumor suppressor gene can be inactivated by hypermethylation of the promoter region in many type of tumors including oral cancer. We recently studied the relationship of inactivation of p16INK4A and tumorigenesis in oral cancer. The aim of the present study was to describe the relationship between macroscopic changes of rat oral mucosa treated with 4-nitroquinoline 1-oxide (4NQO) and an inactivation of p16INK4A. We analyzed the relation of p16INK4A inactivation by hypermethylation of the promoter region of p16INK4A gene using polymerase chain reaction (PCR), PCR-single-strand confirmation polymorphism (PCR-SSCP), and methylation-specific-PCR (MSP). We observed that methylation of p16INK4A genes were rare in mild and moderate dysplasia, but inactivation was observed at high frequency even in severe dysplasia and SCCs in rat carcinogenesis. The expression pattern of p16INK4A protein, detected by western blotting and immunohistochemistry, were similar to the hypermethylation status of the p16INK4A promoter region. Inactivation by hypermethylation of the promoter region of p16INK4A gene was related to carcinogenesis of oral cancer.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Ehime University School of Medicine, Ehime, Japan. nakahara@m.ehime-u.ac.jp
authors.forename: Yuuji
authors.initials: Y
authors.lastname: Nakahara
authors.forename: Satoru
authors.initials: S
authors.lastname: Shintani
authors.forename: Mariko
authors.initials: M
authors.lastname: Mihara
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsumura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hamakawa
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D000818:Animals; D001483:Base Sequence; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D019656:Loss of Heterozygosity; D009061:Mouth Mucosa / Q000187:drug effects / Q000473:pathology; D051381:Rats; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology
chemical_list: D002273:Carcinogens; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D004273:DNA, Neoplasm; D015112:4-Nitroquinoline-1-oxide