Abstract:
Granulosa cell tumours (GCTs) of the ovary are rare tumours that comprise approximately 8% of all the ovarian tumours. The understanding of the pathogenesis of these tumours is limited due to the rarity of these tumours. However, a somatic missense mutation in the FOXL2 gene (c.402C>G, p.C134W), specific to adult GCTs was identified and published work from our laboratory showed that the genes regulated by the mutant FOXL2 protein were found to be significantly enriched for the TGF-β signalling pathway. It was hypothesised from previous studies that deregulation of the TGF-β signalling pathway might contribute towards the pathogenesis of adult GCTs. A recent study identified a TERT promoter mutation (C228T) in recurrent as well as primary adult GCTs. Therefore, the aim of this thesis is to delineate the role of FOXL2 in the alteration of the TGF-β signalling pathway and its effect on TERT. The TGF-β signalling pathway was altered in KGN cells using a known inhibitor (Pirfenidone) and agonist (TGF-β2) of the TGF-β signalling pathway to observe the gene expression and proliferation changes in the KGN cells, that are representative of adult GCTs. Gene knockdown experiments were performed to investigate the role of FOXL2 and TGF-β signalling pathway components and their relationship with each other and TERT. This novel study of the analysis of FOXL2, TGF-β signalling pathway components and TERT demonstrated that TERT is transcriptionally downstream of both FOXL2 and TGFBR2. It has also led us to hypothesise that there may be a feedback loop between FOXL2 and TGFBR2, and that they may regulate the expression of one another, in addition to regulating TERT. More studies need to be carried out in order to fully understand how FOXL2 and the TGF-β signalling pathway may operate in adult GCTs and how they may be linked functionally to TERT, to cause adult GCT pathogenesis and/or recurrence. This research may help us understand the molecular mechanisms responsible for the pathogenesis and recurrence of adult GCTs that might help us target suitable genes for alternative diagnostics and therapeutics.
