Article

Abnormalities of the ARF-p53 pathway in oral squamous cell carcinoma.

Faculty of Dentistry, University of Toronto, 124 Edward St., Toronto, Canada, M5G 1G6.
Oncogene (Impact Factor: 7.36). 03/2001; 20(5):654-8. DOI:10.1038/sj.onc.1204131
Source: PubMed

ABSTRACT Oral squamous cell carcinoma (OSCC) is associated with heavy smoking and drinking, but the molecular pathway of tumorigenesis is not understood. Inactivation of the p53 tumor suppressor gene is likely to play an important role since p53 mutation is frequently found. The p14ARF tumor suppressor gene is functionally linked to p53, because it is activated by oncogenes and causes p53-dependent growth arrest and apoptosis. The relationship between p14ARF and p53 inactivation has not been described for OSCC. We studied 25 cases of OSCC to determine if there is an inverse correlation between p53 mutation and p14ARF inactivation by homozygous deletion or mutation. p53 mutation was found in 16 of 25 cases (64%), including nine missense and seven truncating mutations. While all cases with missense mutations showed abnormal accumulation of p53 protein, there were also five carcinomas which showed increased p53 staining in the absence of mutation. p14ARF deletion or mutation was found in eight cases (32%), six of which also demonstrated p53 mutation. Our findings indicate that OSCC often involves loss of both p14ARF and p53 function and suggest that inactivation of these two tumor suppressor genes are not functionally equivalent during tumorigenesis.

0 0
 · 
0 Bookmarks
 · 
36 Views
  • [show abstract] [hide abstract]
    ABSTRACT: Tobacco and alcohol consumption have been reported as major factors for the development of oral cancer. Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products have many functional secondary metabolites, including monacolin K, citrinin, ankaflavin, and monascin. In several recent studies performed in our laboratory, these secondary metabolites have shown anti-inflammatory, anti-oxidative, and anti-tumor activities. Many published studies have shown the efficacy of Monascus-fermented products in the prevention of numerous types of cancer. The current article discusses and provides evidence to support that Monascus-fermented metabolites may be developed as painting drugs for the mouth to prevent or cure oral carcinogenesis. This is a novel therapeutic approach focusing on tumor growth attenuation to improve patient survival and quality of life.
    Applied Microbiology and Biotechnology 01/2012; 93(5):1831-42. · 3.69 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: We previously reported that dibenzo[a,l]pyrene (DB[a,l]P), the most potent known environmental carcinogen among polycyclic aromatic hydrocarbons (PAH) congeners, is carcinogenic in the oral tissues of mice. We have now developed a new mouse model which employs the oral application of the fjord region diol epoxide, (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE), a metabolite of the tobacco smoke constituent DB[a,l]P, and we show its specific induction of oral squamous cell carcinoma (OSCC) in both tongue and other oral tissues. Groups of B6C3F1 mice (20/group) received 6 or 3 nmol of (±)-anti-DB[a,l]PDE administered into the oral cavity; 3 times per week for 38 weeks. Additional groups received the vehicle alone or were left untreated. Mice were sacrificed 42 weeks after the first carcinogen administration. The high dose induced 74 % and 100 % OSCC in the tongue and other oral tissues, respectively; the corresponding values at the lower dose were 45 % and 89 %. Using immunohistochemistry, we showed that DB[a,l]PDE resulted in overexpression of p53 and COX-2 proteins in malignant tissues when compared to normal oral tissues and tongues. Consistent with the carcinogenicity, we demonstrated powerful mutagenicity in cII gene in B6C3F1 (Big Blue) mouse tongue. The mutational profile in lacI reporter gene is similar to those detected in human head and neck cancer, and p53 mutations were observed in mouse oral tumor tissues. Taken together, we conclude that the formation of diol epoxides plays a major role among the mechanisms by which DB[a,l]P exerts its oral mutagenicity and tumorigenicity. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 03/2013; · 6.20 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Since p14(ARF)and HPV16 E6/E7 oncoproteins are important regulators participating the p53/Rb pathways, genetic variations of p14(ARF) may modify tumor HPV16 status and survival of HPV16-positive SCCOP patients. We determined tumor HPV16 status and expression of p14/p53, and genotyped p14(ARF) rs3731217 and rs3088440 polymorphisms in 552 incident SCCOP patients. We found that patients having variant genotypes for each p14(ARF) polymorphism were approximately twice or three times as likely to have HPV16-positive tumors compared with patients with corresponding common homozygous genotype, and such an association was particularly pronounced in patients with variant genotypes of both polymorphisms. After definitive chemoradiotherapy, patients having p14(ARF) rs3731217 TG/GG variant genotypes had significantly better overall, disease-specific, and disease-free survival than those having TT genotype, respectively. Multivariable analysis found that patients with p14(ARF) rs3731217 TT genotype had an approximately 7, 11, and 3-fold increased risk for death overall, death due to SCCOP, and recurrence than those with TG/GG variant genotypes, respectively. Furthermore, such significantly prognostic effect was also found when survival analysis was limited to HPV16-positive patients. Additionally, potentially functional relevance of the two variants was characterized to explore the genotype-phenotype correlation. Our findings indicate p14(ARF) variants may predict tumor HPV16-positive SCCOP patients and survival.
    Carcinogenesis 10/2013; · 5.64 Impact Factor

Full-text (2 Sources)

View
0 Downloads
Available from
Apr 10, 2014