Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and poses a significant health burden due to its rising incidence. The proto-oncogene PTTG is overexpressed in HNSCC and correlates with poor patient prognosis. A recent unpublished GEO profile eDNA array analysis has further suggested a potential upregulation of its binding partner PBF in HNSCC. PTTG and PBF cause transformation in vitro and tumour formation in vivo, both effects thought to be partly mediated by their interactions with the tumour suppressor protein p53. Dysregulation of the p53 pathway is frequently observed in HNSCC, thus alluding to the importance of functionally active p53 in the suppression of HNSCC initiation and progression. The work presented in this thesis describes the functional relationship between PTTG, PBF and p53 in HNSCC. Initial studies confirmed that PTTG and PBF are overexpressed in HNSCC tumours compared to matched normal tissue. In addition, high tumoural PTTG expression correlated with HPV status, whereas high tumoural PBF expression was associated with a significant gender bias. Further investigations established that PTTG and PBF functionally interact with p53 and cooperate to reduce p53 protein stability in HNSCC cells. Moreover, attenuation of PTTG or PBF expression led to dysregulated expression of p53-related genes involved in DNA repair and apoptosis, indicating that both proto-oncogenes may serve to promote genomic instability and HNSCC cell survival. Functionally, depletion of PTTG or PBF significantly repressed cellular migration and invasion, and impaired colony formation in HNSCC cells. Overall, this research has provided novel insights into the roles of PTTG and PBF in HNSCC tumour initiation and progression, through modulation of p53 activity and function.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:715702 |
| Date | January 2017 |
| Creators | Modasia, Bhavika |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/7574/ |
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