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Title: The regulation of prostate epithelial cell proliferation and migration by PRH/HHEX
Author: Siddiqui, Yusra Hasan
ISNI:       0000 0004 5922 1000
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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Prostate cancer is the most common cancer in men in the UK, and the five-year survival rate drops to thirty percent when this disease has metastasised. PRH/Hhex (Proline Rich Homeodomain protein/Human haematopoetically expressed homeobox) is an oligomeric transcription factor that controls cell proliferation in a variety of tissues. PRH activity is known to be misrelated in several disease states including breast cancer and leukaemia. Recent work has shown that PRH is phosphorylated by protein kinase CK2 (casein kinase 2) in leukemic cells and that this prevents PRH from binding to DNA and regulating transcription. This thesis shows that PRH is expressed in normal immortalised prostate epithelial cells and prostate cancer cell lines. Moreover, PRH is hyper-phosphorylated in the cancer cell lines and inhibition of CK2 activity reduces PRH phosphorylation in normal immortalised prostate cells. PRH knock-down using targeted shRNAs increases the proliferation of normal immortalised prostate epithelial cells whereas over-expression of PRH decreases the proliferation of these cells and prostate cancer cells. Unexpectedly, PRH knock-down also increases the migration of normal immortalised prostate epithelial cells in wound closure assays and Transwell migration assays while PRH over-expression inhibits cell migration. Moreover, PRH over-expression inhibits the ability of prostate cancer cells to migrate through a Matrigel layer in Transwell invasion assays and though an endothelial cell barrier in transendothelial in vitro extravasation assays. The interaction of PRH knock-down cells with platelets was also studied. Platelets are one of the first components to interact with cancer cells when they enter the bloodstream. PRH knock-down cells interact more with platelets than control cells and platelets increase in vitro extravasation of PRH knock-down cells. Data presented here also shows that the regulation of PRH phosphorylation by CK2 influences the proliferation of prostate cells and their ability to migrate and invade. Finally I show that Endoglin, a TGF-β co-receptor, which has been shown in previous studies to inhibit prostate cell migration and invasion, is a direct target for regulation by PRH. Furthermore, the effects of PRH on cell proliferation, migration, and invasion, appear to be mediated in large part at least by Endoglin and its effects on TGF-β signalling. These data suggest that PRH may act as a tumour suppressor in prostate tumourigenesis inhibiting both cell proliferation and the ability of prostate cancer cells to invade and extravasate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available