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Title: Functional characterization of three novel candidate biomarkers and therapeutic targets for prostate cancer
Author: Zhang, Yu
ISNI:       0000 0004 0123 5610
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2010
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Anterior gradient-2 (AGR2), S100A4, and osteopontin (OPN) play important roles in malignant progression of breast cancer. Their possible involvement in prostate cancer had not been full explored previously. The aim of this study was to investigate the expression status of these genes and their diagnostic and prognostic significance in prostate cancer. The possibility of using these candidate genes as targets to suppress tumourigenicity of prostate cancer cells was also investigated. Comparing with the normal and benign cells, expression of AGR2, S100A4 and OPN were greatly increased in malignant prostate cancer cell lines as observed in breast cancer. Immunohistochemical staining of an archival set of more than 100 prostate tissue samples showed that the levels of all these 3 proteins were significantly higher in carcinoma tissues than those expressed in normal and benign tissues. Kaplain Mire Survival analysis of immunohistochemically stained samples showed that high expression of AGR2 and OPN but not S100A4 was significantly correlated with the poor patients' survival time. Thus, all these three molecules were over-expressed in prostate carcinomas and AGR2 and OPN may be useful prognostic markers to predict patient's outcomes. To futher study the roles of S100A4 and OPN in malignant progression, RNAinterference was employed to stably establish S100A4-suppressed and OPN-suppressed clones. When compared with the control, suppression of either OPN or S100A4 signifcantly inhibited cell proliferation, invasiveness, and anchorage-independent growth. Similar results were obtained from in-vivo experiments. S100A4-suppressed and OPN-suppressed cells produced significant reductions in sizes of subcutaneous tumours after inoculation into nude mice. When the levels of OPN and S100A4 were analysed respectively in the tumors produced by both types of transfectants, it was found that it was the suppression of OPN rather than S100A4 that was significantly associated with the reduction in tumor sizes. Hence S100A4 may promote malignant progression of prostate cancer through modulating OPN and thus OPN is a down-stream mediator of S100A4. This result suggested that OPN may be a more effective target for tumour suppression than S100A4 in prostate cancer.
Supervisor: Ke, Y. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral