NQO1 C609T (Pro187Ser) increases risk of carcinogenesis of Oral Submucous Fibrosis by interacting with phosphorylated p53 and cyclin D1

Present study explores the role of NADPH quinone oxidoreductase 1 (NQO1) C609T (Pro187Ser) polymorphism in susceptibility to and its probable role in malignant potentiality of Oral submucous fibrosis (OSF) – a debilitating disease caused mainly by chewing arecanut. About 18% of the patients were detected with minor TT allele (Ser/Ser) p=0.026, while both CT (Pro/Ser) and TT (Ser/Ser) allele, p= 0.003 & 0.004 respectively, was found to be higher in patients above 40yrs of age. NQO1 protein was 42% reduced in buccal tissues of heterozygous (Pro/Ser) carriers, whereas a 70% reduction was observed in TT (Ser/Ser) patients. We detected the expression of p53 (Ser15) which is specifically produced in response to DNA damage and cyclin D1 (CCND1) to be related to NQO1 activity in buccal tissue of patients. A stabilized p53 (Ser15) and low CCND1 was evident in wild type (CC) patients. While a progressive MDM2 mediated degradation phospho p53 (Ser15) and increase in cyclin D1 expression was found in heterozygous (CT) or homozygous (TT) patients with carcinogenic lesions respectively. The present result identifies NQO1 C609T polymorphism as a potential risk in susceptibility to develop OSF. This also explains the event of carcinogenesis which may be attributed by MDM2 mediated degradation of p53 (Ser15) and for the first time reports role of this polymorphism in regulation of CCND1 and thus carcinogenesis of OSF.