Accumulation of inactive p53 protein in oral squamous cell carcinoma: stabilization by protein interaction

Francis, Geo; Kumar, Umesh; Nalinakumari, K.R.; Jayasree, K; Kannan, S.

doi:10.1111/eos.12007

Cited by 9 publications

(3 citation statements)

References 42 publications

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“…Although MDM2 SNP309 is a plausible carcinogenic hereditary factor in the MDM2-p53 pathway, MDM2 is activated in response to a variety of oncogenic pathways that are independent of p53 (22). Furthermore, Francis et al (23) reported that MDM2 has no significant role in stabilizing the expression of p53, and remarked on the presence of unknown interactors that sequester p53 and lead to its aberrant accumulation. Additionally, there is evidence that decreased MDM2 expression is associated with a worse prognosis of head and neck carcinomas (24).…”

Section: Test Of Association Test Of Heterogeneity ------------------mentioning

confidence: 99%

Association of MDM2 promoter T309G polymorphism with oral cancer risk: A meta-analysis of 3,536 subjects

Yang

Zhu

et al. 2016

Molecular and Clinical Oncology

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Abstract. The mouse double minute 2 (MDM2) gene is an important regulator of the p53 suppressor gene. To date, evidence concerning the association of the MDM2 single nucleotide polymorphism (SNP) 309T>G (rs2279744) with the risk of developing oral squamous cell carcinoma (OSCC) remains controversial. Therefore, a meta-analysis of all the eligible studies was performed, in order to derive a more precise estimation of this association. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the degree of association in 5 previous studies, including a total of 1,369 OSCC cases and 2,167 controls. The overall analysis revealed a significant association between MDM2 SNP309 and OSCC risk in the heterozygote (TG vs. TT: OR=0.81; 95% CI: 0.68-0.96; P=0.02) and dominant models (TG+GG vs. TT: OR=0.82; 95% CI: 0.69-0.97; P=0.02). The subgroup analysis based on the source of the controls revealed a significant association between population-based controls and the heterozygote model (TG vs. TT: OR=0.75; 95% CI: 0.62-0.91; P=0.004), dominant model (TG+GG vs. TT: OR=0.76; 95% CI: 0.63-0.91; P=0.003) and allele comparison (G vs. T: OR=0.89; 95% CI: 0.79-0.99; P=0.04). Importantly, no evidence of publication bias or obvious heterogeneity were observed in the meta-analysis. The results of the present study demonstrated a decreased risk of developing OSCC for the MDM2 SNP309 group, suggesting MDM2 SNP309 may be a protection-associated genetic variation for OSCC. Additional well-designed studies, with larger sample sizes, are required to further elucidate this association. IntroductionOral cancer is one of the most common cancers worldwide, with an unclear pathogenesis; the oral squamous cell carcinoma (OSCC) subtype accounts for >90% of all oral cancers (1). While increasing evidence suggests that environmental factors, as well as chemical carcinogens (including tobacco and alcohol) are likely etiological factors that contribute to the development of OSCC, only a small minority of individuals exposed to these carcinogens will subsequently develop head and neck SCC (2,3). Oral carcinogenesis is widely recognized as a stepwise process, and the involvement of genetic alterations and host polymorphisms may be important to its development (4). The identification of a predictive model of risk polymorphisms may facilitate early diagnosis and the understanding of disease progression in a subset of cancer patients (4).The human mouse double minute 2 (MDM2) gene is an important negative regulator of the p53 suppressor gene, promoting the degradation of p53 through its E3 ubiquitin ligase activity (5). A functional single-nucleotide polymorphism (SNP), rs2279744, is located at nucleotide 309 in the first intron of the MDM2 promoter region, consisting of a change from T to G. This mutation has been named SNP309 (6). SNP 309T>G is known to enhance the binding affinity of the transcriptional activator SP1, contributing to increased expression of MDM2 and subsequent attenuation of the p53 tumor suppressor pathway (6). MDM2 SNP3...

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Section: Test Of Association Test Of Heterogeneity ------------------mentioning

confidence: 99%

Association of MDM2 promoter T309G polymorphism with oral cancer risk: A meta-analysis of 3,536 subjects

Yang

Zhu

et al. 2016

Molecular and Clinical Oncology

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“…In our study cohort, only 2 out of 103 OSCC samples analyzed showed HPV infection. Furthermore, these samples harbored wild-type TP53 and high TP53 protein levels, indicating lack of association between HPV infection and oral carcinogenesis, at least in our study cohort (Francis et al, 2013).…”

Section: Discussionmentioning

confidence: 64%

Novel mutations and expression alterations in SMAD3/TGFBR2 genes in oral carcinoma correlate with poor prognosis

Sivadas

George

Jayasree

et al. 2013

Genes Chromosomes & Cancer

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Transforming growth factor beta (TGF-β) signaling is a pleiotropic cytokine signaling pathway, which controls cellular activities ranging from embryogenesis to apoptosis. Although many molecular alterations in this pathway have been described in cancers, the central point of concern, that is how these alterations influence the treatment outcome, has been addressed to a lesser extent. In this study, we have characterized the alterations of TGF-β-SMAD signaling in 97 oral squamous cell carcinoma (OSCC) samples and assessed the association between these alterations and the outcome of the treatment. Genomic level alteration analysis using reverse transcriptase polymerase chain reaction-single-strand conformation polymorphism/sequencing revealed that there were 25% samples harboring genomic level alterations in this pathway. Altogether, 21% samples showed TGFBR2 mutations, whereas three cases were found to harbor novel SMAD3 mutations. Notably, 14 out of 24 TGFBR2 mutations are of one type (c.*6C>A), which supplemented complementarity for hsa-miR-3189-5p. These samples showed significantly low TGFBR2 transcript levels (P = 0.026). In addition, transcript level studies using quantitative real-time PCR revealed a strong association between low TGFBR2 transcript levels and poor disease-free survival (P = 0.028) as well as poor overall survival (P = 0.013). In brief, our results showed that oral cancers with TGFBR2 downregulation comprise a different group with more aggressive nature. These results suggest that in OSCCs, TGFBR2 transcript levels may be developed as a promising prognostic biomarker. Furthermore, for the first time, this study reports SMAD3 mutations in oral carcinoma.

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“…Initially, the molecular alterations in oral keratinocytes may not be expressed as clinical or histological lesions, increasing the risk of malignant transformation, which has been referred to as field cancerization, as proposed in 1953 by Slaughter et al [ 83 ]. Field cancerization is clinically relevant in the prevention of groups of patients at high risk of developing oral cancer [ 84 , 85 ], because early genomic alterations, including microsatellite alterations, mutations in p53 and chromosomal instability, have been evidenced in otherwise histologically normal epithelium, adjacent to oral carcinomas [ 86 , 87 ]. The detection of genetically altered cells from clonal populations with increased growth and high proliferative rates indicate that lateral clonal extension is frequent in potentially malignant or invasive lesions.…”

Section: Altered Wnt/β-catenin Signaling In Oral Carcinogenesismentioning

confidence: 99%

Wnt/β-Catenin Signaling in Oral Carcinogenesis

Reyes

Flores

Betancur

et al. 2020

IJMS

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Oral carcinogenesis is a complex and multifactorial process that involves cumulative genetic and molecular alterations, leading to uncontrolled cell proliferation, impaired DNA repair and defective cell death. At the early stages, the onset of potentially malignant lesions in the oral mucosa, or oral dysplasia, is associated with higher rates of malignant progression towards carcinoma in situ and invasive carcinoma. Efforts have been made to get insights about signaling pathways that are deregulated in oral dysplasia, as these could be translated into novel markers and might represent promising therapeutic targets. In this context, recent evidence underscored the relevance of the Wnt/β-catenin signaling pathway in oral dysplasia, as this pathway is progressively “switched on” through the different grades of dysplasia (mild, moderate and severe dysplasia), with the consequent nuclear translocation of β-catenin and expression of target genes associated with the maintenance of representative traits of oral dysplasia, namely cell proliferation and viability. Intriguingly, recent studies provide an unanticipated connection between active β-catenin signaling and deregulated endosome trafficking in oral dysplasia, highlighting the relevance of endocytic components in oral carcinogenesis. This review summarizes evidence about the role of the Wnt/β-catenin signaling pathway and the underlying mechanisms that account for its aberrant activation in oral carcinogenesis.

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Accumulation of inactive p53 protein in oral squamous cell carcinoma: stabilization by protein interaction

Cited by 9 publications

References 42 publications

Association of MDM2 promoter T309G polymorphism with oral cancer risk: A meta-analysis of 3,536 subjects

Association of MDM2 promoter T309G polymorphism with oral cancer risk: A meta-analysis of 3,536 subjects

Novel mutations and expression alterations in SMAD3/TGFBR2 genes in oral carcinoma correlate with poor prognosis

Wnt/β-Catenin Signaling in Oral Carcinogenesis

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