Molecular Characterization of ‘p53 Family Network’ in Human Head and Neck Cancer and Anti-EGFR Therapy
Sebastian, Sinto (2008) Molecular Characterization of ‘p53 Family Network’ in Human Head and Neck Cancer and Anti-EGFR Therapy. [Tesi di dottorato] (Inedito)
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Understanding of p53 family protein (p53, p63 and p73) networks in head and neck squamous cell carcinoma (HNSCC), can positively influence in cancer screening, diagnosis, treatment and prevention. P53 family proteins are regulating diverse cell signalling pathways at diverse conditions to determine cell fate. At each condition of cells state, how these proteins are controlling cell fate is more complexed due to the presense of several isoforms for each p53 family proteins and their multifaceted interactions. Like other solid tumours, the p53 pathway is disabled by several mechanisms in HNSCC. Despite of the convincing evidence of a high frequency of p53 mutations in HNSCC, a subset of cancers arise in the absence of mutations. The molecular mechaninsms through which p53 lacking mutations subvert its tumor supressor functions in HNSCC still remain uncertain. In fact, some cancers and established cancer cell lines are over-expressing wild type p53 protein makes questionable of p53 role as only a tumor suppressor or it has some other additional functions, even in cancer cells. For an answer of this hypothesis, we have performed detailed molecular characterization, in an invitro model of head and neck cancer, in a broad panel of 12 newly established HNSCC cell lines. In our studies, we found that some head and neck cancer cell lines are accumulating wild p53 protein hyperphosphorylated at serine15 and 392 and it leads to the over expression of DNp73, the mechanism already reported from our laboratory in HPV38 immortalized keratinocytes. To better understand the functions of accumulated wild p53 role in HPV positive and negative cancer cell lines, we have performed p53 knock down by siRNA and the results have showed that p53 knock down inhibited cell proliferation in both HPV positive and negative cancer cells. Moreover, p53 knock down induced significant morphological changes and senescence associated beta galactosidase activity in these cells. Our results pinpoint, wild-type p53 protein accumulated in transformed cell lines has an additional role in cell proliferation other than its well known tumor supressor activity. Moreover, the key role of p53 family network in modulating epidermal growth factor receptor (EGFR) expression and in controlling cell proliferation and apoptosis arises the question of whether p53 family proteins status influences the efficacy of EGFR inhibitors, investigating its ability to reduce cell growth, to induce apoptosis and to modulate cell cycle and various EGFR pathwayrelated targets in head and neck cancer. Because, recently improved understanding of the pathogenesis of human head and neck squamous cell carcinoma has led to the development of new, molecular based therapeutic strategies, one of the most promising is the utilization of tyrosine kinase (TK) inhibitors, targeting EGFR. The comparison between the targets analysed and gefitinib effectiveness evidenced the absence of a clear relationship, exluding them as predictive factors for gefitinib efficacy. Our results confirmed the in vitro efficacy of an anti-EGFR approach, but other targets than those analysed here should be characterized in order to identify valid predictive factors for gefitinib utilization in head and neck cancer. We have also performed chemoresistance analysis in our invitro model of HNSCC cell lilnes and found that p53 family network has less predictive role in HNSCC chemoresistance but ABCG2, a multidrug resistance protein, has over-expressed in HNSCC.
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