MDM2 Overexpression with Alteration of the p53 Protein and Gene Status in Oral Carcinogenesis

Abstract

In this study, to better understand the mechanism of oral squamous cell carcinoma (SCC) carcinogenesis, alterations of the p53 gene and overexpression of MDM2 and p53 were analyzed in 38 oral SCC samples. Twelve of the 38 specimens revealed mutant-type p53. Moreover, coexpression of MDM2 and p53 was found most frequently in dysplastic lesions (P < < < <0.05). Expression of MDM2 and p53 was significantly increased in accordance with the histological progression of multistep carcinogenesis (P < < < <0.05). No significant correlation was found between the expression of MDM2 and the alteration of p53 protein or p53 gene status. MDM2 overexpression with mutant p53 was significantly associated with poorly differentiated SCCs (P < < < <0.05) and tumor stages III and IV of oral SCCs (P < < < <0.05). These results suggest that MDM2 overexpression is an early event in oral carcinogenesis through the functional inactivation of the wild-type p53, and corresponding alterations of MDM2 and p53 contribute to the oral carcinogenesis. We propose that it would be clinically more instructive to evaluate MDM2 overexpression combined with p53 gene status, compared to the evaluation of either MDM2 or p53 alteration alone. Key words: MDM2 -p53 -Oral carcinogenesisOral squamous cell carcinoma (SCC) is the most common malignant tumor in the oral cavity.1) Nevertheless, the mechanism of oral carcinogenesis is still poorly understood.2) Previous studies have shown that inactivation of wild-type p53 function by mutation or interaction with a viral oncogene product plays an important role in carcinogenesis, including oral SCC.3-6) However, there are still oral SCCs which do not contain mutant p53 or viral protein. Therefore, it is reasonable to assume the presence of a p53-independent oral carcinogenesis pathway.It was found that MDM2, a cellular oncogene product, can bind to the p53 N-terminal acidic domain to inactivate its transcription factor activity.7, 8) Also, p53 can bind to the first intron of the MDM2 gene to activate MDM2 transcription, thus establishing a negative feedback loop 9) to control the cell cycle.MDM2 can inhibit wild-type p53-mediated G1 arrest and apoptosis.10, 11) MDM2 also plays a role in promoting the S phase in the p53-independent pathway.12) It has been reported that overexpressions of both p53 and MDM2 are more frequent in high-grade bladder cancer.13) MDM2 overexpression is observed in various tumors with or without p53 mutation.14-17) However, the significance of the correlation between the overexpression of MDM2 and the p53 status in the multistep processes of oral SCC development has not yet been clearly elucidated. 18)In this study, to reach a better understanding of the mechanism of oral carcinogenesis, the alterations of the p53 gene in oral SCC specimens were investigated. Furthermore, using the same specimens, the overexpression of MDM2 and p53 was analyzed in normal mucosa adjacent to the tumor, and in premalignant and malignant lesions. MATERIALS AND METHODS MaterialsThe 38 oral SCC specimens used in...

P53/MDM2 co-expression correlates with the tumour differentiation in oral squamous cell carcinoma - a retrospective study and a systematic review

“…These results suggest the existence of a p53-independent MDM2 regulatory pathway (29) and that these pathways may also be important in OSCC (26). Furthermore, it shows that the functional status of p53 is not the only factor that determines the expression of MDM2 (26). This is further supported by the study of Ralhan et al (2000), where three different isoforms of MDM2 proteins (i.e.…”

“…This is in contrast to the systematic reviewed studies by Agarwal et al (1999), Shwe et al (2001) and Yanamoto et al (2002) but similar to other studies by Ng et al (1999), Li et al (2000) and Liu et al (2004) that did not show any significant correlation between the co-expression and the lack of coexpression of p53/MDM2. These results suggest the existence of a p53-independent MDM2 regulatory pathway (29) and that these pathways may also be important in OSCC (26). Furthermore, it shows that the functional status of p53 is not the only factor that determines the expression of MDM2 (26).…”

“…In the present study, the over-expression of p53 was seen in only 34 cases (75.6%). Most of the studies have shown MDM2 to be over-expressed in more number of cases studied than p53 except Ng et al (1999), Regezi et al (1999), Li et al (2000), Sano et al (2000) and Yanamoto et al (2002) where p53 was expressed in more number of cases (Table 5a). These discrepancies could be explained by the fact that, factor other than p53 regulates MDM2 (24).…”

Therapeutic Efficacy of p53 Restoration in Mdm2-Overexpressing Tumors

“…More interestingly, patients with tumors carrying both alterations generally show more malignant disease and poorer prognosis, compared to the ones with tumors bearing either alteration alone (17, 21, 23, 24). These observations suggest that alterations in both Mdm2 and p53 may confer additional growth advantages to tumor cells.…”

Carcinoma escamoso basalóide na mucosa bucal: comportamento clínico, prognóstico e análise da expressão de PCNA, p53, BAX e BCL-X

“…1992, corroborando com a designação proposta por WAIN et al 131 12,61,85,86,87,108 . Entre os parâmetros utilizados neste painel, verifica-se a combinação da expressão da proteína p53 com: a morfologia tumoral, a proliferação celular, as proteínas reguladoras dos pontos de checagem durante o ciclo celular como a ciclina D1, cdk4, p21, p27, mdm2, pRb 4,39,49,55,61,65,70,82,91,103,121 e com as proteínas reguladoras dos processos apoptóticos 77,78,106 .…”