Prostate cancer (PCa) is the second most common and second leading cause of cancer-related deaths of men in the UK. In its localised form, PCa has a high long-term survival rate. However, 90% of patients with advanced PCa eventually develop metastases which account for the majority of PCa deaths. Despite this, how prostate cancers metastasise is poorly understood. Rho GTPases are known to contribute to cancer progression. Investigation of mutations of Rho GTPases, and their regulators and effectors in prostate- derived cell lines revealed that Rho GTPases themselves are not frequently mutated, but their regulators and effectors are. The Rho GTPase RhoH is highly expressed in haematopoietic cells and has been shown to regulate T-cell migration. Interestingly, RhoH was found to be expressed in several PCa and breast cancer cell lines and in the PCa cell line PC3 it increases cell migration. In this study, the role of RhoH in PCa cells was investigated in PC3 and DU145 cell lines using the analysis of online datasets, 2D/3D live and confocal imaging, adhesion assays, and western blotting. Results suggest that although RhoH is not commonly mutated in PCa, its over-expression or depletion induces clear phenotypes related to cell migration and invasion. RhoH affects cell shape in both cell types. Knockdown of RhoH in PC3 cells results in increase in cell area, while overexpression of RhoH in PC3 and DU145 cells results in cell elongation. RhoH also affects cancer cell adhesion to endothelial cells, implicating a role in the extravasation step in metastasis. Preliminary work also suggests that RhoH might act downstream of the HGF signalling pathway, as RhoH depletion reduces PC3 cell elongation in 3D in response to HGF stimulation. Still, the signalling pathway through which RhoH acts in PCa cells is unknown and warrants further investigation.
|Date of Award||26 Nov 2020|
- The University of Bristol
|Supervisor||Eugenia Piddini (Supervisor) & Anne J Ridley (Supervisor)|