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

Article (PDF Available)inOncogene 20(5):654-8 · March 2001with12 Reads
DOI: 10.1038/sj.onc.1204131 · Source: PubMed
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.
    • "Pidd mRNA levels were measured by quantitative real-time RT- PCR in 24 cases of OSCC with known p53 mutation status. There were 16 cases with p53 mutation, including nine missense mutations affecting exons 5 – 8, four mutations to STOP codon and three frameshift mutations due to single-base pair insertion or deletion in exons 3 – 5. Twenty out of the 24 cases have been previously reported in a study on p53 and p14ARF abnormalities in OSCC (Bradley et al, 2001). There was no correlation between Pidd mRNA levels and p53 mutation status.Figure 5 illustrates the distribution of Pidd expression in OSCC with and without p53 mutation, and in normal oral epithelium from patients with no history of OSCC. "
    [Show abstract] [Hide abstract] ABSTRACT: The Pidd (p53-induced protein with death domain) gene was shown to be induced by the tumour suppressor p53 and to mediate p53-dependent apoptosis in mouse and human cells, through interactions with components of both the mitochondrial and the death receptor signalling pathways. To study the role of Pidd in clinical tumours, we measured its expression by quantitative reverse transcription-PCR in microdissected oral squamous cell carcinomas (OSCC) with and without p53 mutation. Tumour cell apoptosis was assessed by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling. Tumour proliferation was assessed by immunohistochemical staining for the Ki-67 antigen. We found a wide range of Pidd expression among OSCC. Statistical analysis revealed an association between Pidd expression and apoptotic index (Mann-Whitney test, P<0.001), consistent with a role of Pidd in apoptosis in this tumour type. Furthermore, we showed a positive correlation between apoptotic index and proliferative index that has not been previously described for OSCC. There was no correlation between Pidd expression and the p53 mutation status of these tumours, suggesting that Pidd expression may be regulated by p53-independent mechanisms. Further characterisation of these molecular defects in the control of proliferation and apoptosis should help in developing treatments that target OSCC according to their biological properties.
    Full-text · Article · May 2007
    • "While compelling evidence supports a p53-dependent role of p14 ARF in tumor suppression, it has become clear recently that ARF also inhibits cell proliferation in the absence of p53 [27– 31]. Both p53 and p14 ARF are targeted for mutation in oral squamous cell carcinoma [32]. Mice deficient for p19 ARF develop more fibrosarcomas than lymphomas, the reverse of the tumor spectrum displayed by p53-null mice [33]. "
    [Show abstract] [Hide abstract] ABSTRACT: While p14(ARF) suppression of tumorigenesis in a p53-dependent manner is well studied, the mechanism by which p14(ARF) inhibits tumorigenesis independently of p53 remains elusive. A variety of factors have been reported to play a role in this latter process. We report here that p14(ARF) displays different effects on the anchorage-dependent and -independent growth of p53-null/Mdm2 wild type cells. p14(ARF) blocks both the anchorage-dependent and-independent (soft agar) proliferation of 293T and p53(-/-) HCT116, but not p53-null H1299 lung carcinoma cells. While p14(ARF) had no effect on the anchorage-dependent proliferation of p53(-/-) MEFs and Ras12V-transformed p53(-/-) MEFs, it inhibited the growth of Ras12V-transformed p53(-/-) MEFs in soft agar. Furthermore, ectopic expression of p14(ARF) did not lead to degradation of the E2F1 protein and did not result in the reduction of E2F1 activity detected by two E2F1 responsible promoters, Apaf1 and p14(ARF) promoter, in 293T, p53(-/-) HCT116, and H1299 cells. This is consistent with our observations that p14(ARF) did not result in G1 arrest, but induced apoptosis via Bax up-regulation. Taken together, our data demonstrate that the response of p53-null cells to ARF is cell type dependent and involves factors other than Mdm2 and E2F1.
    Article · Sep 2006
    • "Evidence of a molecular cause for the evasion of apoptosis in human tumors was first demonstrated in follicular lymphomas and consisted of increased expression of bcl-2 [48]. Mechanisms of apoptotic resistance in OCSCC include mutations in p53 and bcl-2 and its family-member proteins, overexpression of nuclear factor kappa B or AKT pathway activation [49] [50] [51]. Potential therapeutic strategies to potentiate apoptosis in tumors that target these mechanisms are currently being investigated. "
    [Show abstract] [Hide abstract] ABSTRACT: Significant advances have been made in understanding the mechanisms that contribute to carcinogenesis in OCSCC. This progress has led to the development of therapeutic strategies that target dysregulated processes in the tumor microenvironment (Fig. 11) [72]. The introduction of angiogenesis inhibitors, growth factor receptor tyrosine kinase inhibitors, and cell cycle regulators into clinical trials for the management of OCSCC has resulted from the great strides made in the understanding of tumor biology. It is important for those caring for patients who have OCSCC to have a firm background in tumor biology, because many future therapies will be based on this complex panorama of cellular physiology.
    Article · May 2006
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