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Title: A dynamic transcriptome technique for transcriptional profiling and gene regulatory network involving the helicase antigen (HAGE)
Author: Linley, A. J.
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2010
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Increased knowledge into the molecular pathways disrupted in tumours has led to the development of various therapies that can target specific mediators of these cascades. Such therapies have proven successful in patients or demonstrate significant potential for clinical use. However, this better understanding is undermined by the continued prevalence of cancer and the limitations of these drugs. Therefore, it is possible signalling networks could be influenced by as yet unknown molecules or known mediators with function that have not yet been described. As a result of this, work must continue to improve knowledge yet further to allow the design of novel therapies to aid in the treatment of cancer patients. In the present study, work was performed on the helicase antigen (HAGE), a cancer/testis (CT) antigen and DEAD-box protein found to be present in numerous types of malignancy. As with the majority of CT antigens, the role of HAGE remains unclear. In this instance, studies were carried to discover the function of HAGE in malignant cells. Preliminary in vitro proliferation studies following HAGE gene knockdown or cDNA transfection strongly indicated an association between HAGE expression and increased tumour cell proliferation. This was supported by results gained from in vivo work performed within an immuno-compromised murine model. Expression profiling analysis of data gained from using the Genechip oligonucleotide microarray platform found significant changes to genes linked not only with proliferation but other cell processes altered during tumorigenesis. Confirmation using real-time qPCR suggested change in expression of certain genes could be recognised in other HAGE-expressing tumour cell lines. This analysis also indicated a possible interaction between HAGE and the oncogene N-RAS. Subsequent genetic and protein studies implicated HAGE acting upstream of N-RAS, markedly increasing the N-RAS level in cells. Very preliminary work has begun to demonstrate a role not just in proliferation, but in immune escape, apoptosis inhibition and metastasis, all processes potentially influenced by the RAS oncogenes. The data presented here strongly supports the hypothesis of HAGE having a significant role in malignant biology and warrant continued investigation to further confirm its role in cancer and possibly use as a target for malignancy in the future.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available