It has been hypothesised that MTf may participate in melanoma progression due to the fact that the MTf plays a vital role in proliferation and tumorigenesis. This suggestion has been supported by the high levels of MTf expression in melanoma cells and the fact that previous studies demonstrated silencing MTf decreased melanoma tumour xenograft growth in vivo. In contrast, N-myc downstream regulated gene 1 (NDRG1), is a potent metastasis suppressor and acts to inhibit several oncogenic pathways, such as WNT, PI3K/AKT, etc.
This thesis sought to elucidate the mechanism of MTf activity as a novel pro-oncogenic signalling protein involved in melanoma pathogenesis and whose molecular mechanism(s) of action remain unclear.
Since metastasis accounts for most cancer deaths and is a major problem in melanoma, it was critical to further discover the molecular mechanisms that underlie NDRG1’s ability to inhibit progression and metastasis of melanoma. Furthermore, this thesis examined a promising anti-metastatic therapeutic strategy by assessing the novel, clinically trialled, anti-cancer agent, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which potently up-regulates NDRG1 in a variety of tumour cells.
This dissertation consists of 6 chapters: A comprehensive literature review in Chapter 1 and a general materials and methods chapter (Chapter 2). This is followed by 3 results chapters, namely: Chapter 3 examining the inter-relationship between NDRG1 and MTf in vitro and in human melanoma samples; Chapter 4: exploring the effect of MTf on the crucial upstream receptors of WNT- and PI3K signalling, including LRP6, c-Met, VEGFR2 and FGFR1; and Chapter 5 understanding how MTf drives proliferation and activates these oncogenic pathways when c-Myc is silenced. These chapters are then followed by Chapter 6, which is a general discussion of findings and future directions.