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Investigating the roles of CD44 and CD147 in prostate cancer metastasis and drug-resistance Jingli Hao A Thesis submitted for the Degree of Doctor of Philosophy St. George Clinical School Faculty of Medicine University of New South Wales April 2012 ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….................. COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed ……………………………………………........................... Date ……………………………………………........................... AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Signed ……………………………………………........................... Date ……………………………………………........................... Abstract Prostate cancer (CaP) is a major health problem in males in western countries. Although early-stage CaP can be controlled using conventional therapies, almost all CaP patients invariably progress to recurrent castration resistant CaP and eventually die from secondary disease. Targeting tumour-associated antigens is fast emerging as an area of promise for late stage CaP. This thesis provides an overview of literature regarding CaP-related issues, with emphasis on the putative roles of the tumour microenvironment and selected tumour-associated antigens, i.e. CD44 and CD147 in CaP. The aims of the study were to: 1) investigate the expression of CD44 and CD147 in primary CaP tissues and various metastatic CaP cell lines, and identify whether CD44 and CD147 are related with CaP progression, whether they are related with multidrug-resistance proteins, and whether these two proteins are inter-related; 2) develop CaP cell lines with down- regulated CD44 and CD147 expression, study the in vitro functions of these molecules in CaP, and the potential mechanisms involved; and 3) develop CaP animal models with CD44/CD147-knock-down (KD) xenografts, and look at the roles of CD44 and CD147 in vivo in respect of tumour growth, metastasis, and drug resistance. The results indicated that CD44 and CD147 are both associated with CaP progression. CD44 and CD147 are co-expressed and interact in CaP cells. KD of CD44 or CD147 enhanced docetaxel sensitivity, reduced CaP invasive potential, and down-regulated main signal modulators associated with cell growth and survival. In vivo, CD44 or CD147-KD PC-3M-luc subcutaneous xenografts showed suppressed tumour growth with increased docetaxel responsiveness compared to control xenografts. Preliminary studies of an intracardiac model showed metastatic spread of PC-3M-luc cells imaged using bioluminescence, indicating this is an appropriate model for future studies assessing the in vivo roles of CD44 and CD147 in tumour spread. These findings suggest that CD44 and CD147 are both closely related with CaP metastasis and drug resistance. Selective targeting of CD44/CD147 alone or combined with docetaxel may limit CaP metastasis and increase chemosensitivity, indicating promise for future CaP treatment. To date, these studies appear to be the first to show that CD44 and CD147 are collaborators in CaP. 4 Acknowledgements I‟m greatly indebted to my supervisor Associate Professor Yong Li, whose support, encouragement and help has been invaluable for the thesis and for my development as a researcher at large. In particular, he supported me during all my research work, encouraged me to apply for several awards and travel grants, encouraged me to go to international and domestic conferences and taught me a lot about how to improve my observations, basic experimental skills, manuscript writing, conference presentation and response to all comments. He reviewed my papers and thesis with a lot of patience and actively sought collaborations which supported my skill development. Without him I could not have written this thesis. My co-supervisor Dr. Michele Madigan has always kindly given me the most sincere advice on not only studying but life in general. She always took time out of her busy schedule to discuss with me about scientific problems and the progress of my project. She always carefully reviewed my papers or thesis, or giving hands on demonstrations to develop my experimental skills. Michele, I‟m lucky to have you as my co-supervisor! I am also grateful to my co-supervisor Dr. Aparajita Khatri. I worked under her supervision during the 2nd year of my PhD in the Oncology Research Center (ORC) in the Prince of Wales Hospital. She imparted a tremendous amount of knowledge about molecular biology on me. Thanks Aparajita for providing a very good research environment for me. I also learned a lot from her Post-doctoral Fellows and Research Assistants. I would like to thank them as well: Dr. Nirupama Verma, Ms. Swapna Joshi, Ms. Xiaochun Wang, and Mr. Zhe Yuan. I made good progress when I was working there. Without them I could not have done so. The animal experiments and the preparation for them greatly benefitted from the help I received from Dr. Carl Power and Dr. Tzong-Tyng Hung. They gave me lots of helpful advice, from ethics applications, experiment designing, experiment techniques, to data analysis. I also learned a lot from them about animal experiments and research ethics. Without them, the animal experiments would not have been completed. I also want to say thank you to Professor Pamela Russell, who kindly introduced me to her research group in the ORC and for sharing her precious research resources with us. To all staff in the Oncology Research Center, the help with all little things is greatly appreciated. 5 I also would like to thank Dr Paul Cozzi at the Urology Sydney and Professor Warick Delprado at the Douglass Hanly Moir Pathology, for kindly providing prostate cancer and benign prostatic hyperplasia (BPH) tissues and clinical data for my study. Otherwise, I could not complete my studies on the primary CaP. In addition, I thank all funding bodies including NHMRC, Cancer Institute NSW, St George and Southerland Medical Research Foundation, Urology Research Fund and Cancer Care Centre Cancer Research Trust Fund for their generous supports. I appreciate all supports from the administrative staff at the St George Clinical School, UNSW and the Cancer Care Centre at St George Hospital (Associate Professor Peter Graham and Professor John Kerasley). Further, I want to thank Ms. Julia Beretov, who helped me with all histology preparation related studies. I want to thank my colleagues and friends in the prostate cancer group in St. George Hospital: Dr. Hongmin Chen, Dr. Hongtu Chao, Dr. Weiwei Xiao, and Dr. Jingjing You, we share happiness and sadness together and help each other to go through difficulties in studying and living. Last but not least, I want to thank my beloved family, my husband Josef who always stands by my side and gives me powerful support. He is not only my partner but also my best friend. I want to thank my parents, Lanyun Hao and Shuangzhen Zhao, for their unlimited love and support through out my life. 6 Publications, Presentations and Awards Publications arising from this thesis Hao JL, Cozzi PJ, Khatri A, Power CA, Li Y. EMMPRIN/CD147 and CD44 are potential therapeutic targets for metastatic prostate cancer. Curr Cancer Drug Targ 2010;20:287-306 (IF: 4.8) Hao JL, Chen HM, Madigan MC, Cozzi PJ, Beretov J, Xiao W, Delprado WJ, Russell PJ, Li Y. Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters (MCTs) is related with prostate cancer drug resistance and progression. Br J Cancer 2010;103:1008-1018 (IF: 4.8) Hao JL, Madigan MC, Khatri A, Power CA, Hung TT, Beretov J, Xiao W, Cozzi PJ, Graham PH, Kearsley JH, Li Y. CD44 and CD147 modulate prostate cancer cells in vitro and in vivo metastasis and chemoresistance. Submitted to PLoS ONS in a revised version 2012 (IF: 4.4) Book Chapter: Hao JL, Madigan MC Cozzi PJ, Kearsley J, Li Y. Angiogenesis, lymphangiogenesis and vasculogenic mimicry in human prostate cancer therapy. In: Advances in Medicine and Biology. Editor: Leon V. Berhardt. Volume 38. Nova Science Publishers, Inc. USA. Accepted on 31/03/2011 in press. Other publications: Chen H, Wang L, Beretov J, Hao JL, Xiao W, Li Y. Co-expression of CD147/EMMPRIN with monocarboxylate transporters and multiple drug resistance proteins is associated with epithelial ovarian cancer progression.

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