Vasileios Papanikolaou1, Efthymios Kyrodimos1, Evangelos Tsiambas2, Aristeidis Chrysovergis1
11st ENT Department, Hippocration Hospital, University of Athens, Athens, Greece;
2Department of Pathology-Cytology, 401 General Army Hospital, Athens, Greece.
Abstract
Dear Editor,
Cell cycle deregulation leads progressively normal epithelia to their neoplastic transformation. P53 is a key regulator of the genome stability and function. The gene is located on the short (p) arm of chromosome 17 at position 13.1 (17p13.1) encoding a nuclear phosphoprotein with a molecular mass of 53 kDa acting as a transcription factor that negatively regulates cell proliferation. It is also involved in a significant number of cell signaling pathways including cell cycle, programmed cell death, and DNA repair. Murine double minute 2 (MDM2), a proto-oncogene (12q14.3) encoding a nuclear-localized E3 ubiquitin ligase, acts as a major negative regulator in p53-MDM2 auto-regulatory pathway. MDM2 directly binds to p53 and represses its transcriptional activity and promotes p53 proteasomal degradation. Aberrant p53/MDM2 over expression is a frequent observation in breast carcinomas [1]. Gene amplification is the major mechanism of MDM2 deregulation and overexpression in breast carcinoma correlated with aggressive phenotype [2]. Concerning laryngeal squamous cell carcinoma (LSCC), a study group co-analyzing the expression patterns of p53, its upstream regulator MDM2, and also p21/WAF molecule concluded that p53 mainly and MDM2 aberrant expression could be used as markers for inferior and worse prognosis (overall survival), respectively [3]. Interestingly, specific genetic imbalances (gene polymorphisms) regarding MDM2 gene seem to be associated to increased risk for LSCC onset. A study group implemented a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol for the detection of specific MDM2 polymorphisms (MDM2 rs769412 and MDM2 rs937283). They observed that both of the analyzed polymorphisms were correlated with high susceptibility to LSCC rise and progression, especially in sub-groups of patients with a history of chronic alcohol consumption [4]. Similarly, another study group based on a combination of pyrosequencing and enzyme-linked immunosorbent assay (ELISA) analyzed the status of a specific single-nucleotide polymorphism (SNP) 309T/G SNP in the promoter region of MDM2 and measured MDM2 plasma levels, respectively [5]. They observed that the MDM2 SNP309 G allele acts as a significant LSCC and vocal leukoplakia inhibition genetic marker in the Chinese population, whereas GT type patients correlated with a lower plasma MDM2 level than the TT genotypes. In these patients, a low stage and metastatic potential was also observed. The previous referred molecular data show that deregulation of p53/MDM2 pathway is critical for LSCC rise and progression involved in the early genomic instability of normal laryngeal epithelia. In this model of gene co-reaction, a suppressor gene (p53) is downregulated combined with an oncogene (MDM2) overactivation.
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