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ARPC1B Gene: As a Potential Novel Prostate Cancer Driver

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ARPC1B Gene: As a Potential Novel Prostate Cancer Driver University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2019-12 ARPC1B Gene: As a Potential Novel Prostate Cancer Driver Zaaluk, Hend Hend, Z. (2019). ARPC1B Gene: As a Potential Novel Prostate Cancer Driver (Unpublished master's thesis). University of Calgary, Calgary, AB. http://hdl.handle.net/1880/111382 master thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY ARPC1B Gene: As a Potential Novel Prostate Cancer Driver by Hend Zaaluk A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE GRADUATE PROGRAM IN BIOCHEMISTRY AND MOLECULAR BIOLOGY CALGARY, ALBERTA DECEMBER, 2019 © Hend Zaaluk 2019 Abstract Prostate cancer is the most common malignancy in men and the second leading cause of cancer- related deaths in western countries. Currently, there is a lack of specific molecular markers that can predict cancer progression and prognosis. Characterization of prostate cancer driver genes is essential for investigating the cellular changes that influence the progression of cancer. This will provide a better understanding to prostate cancer carcinogenesis, elucidate novel biomarkers, and improve clinical outcomes. Previously our lab performed a bioinformatics screen using several public cohorts and identified a panel of genes that are deregulated on the mRNA and DNA levels. We hypothesize that these gene are potentially acting as oncogenes and tumor suppressors that could be related to the prognosis of prostate cancer. Actin-related protein -2/3 subunit B (ARPC1B) was found to be one of the most highly dysregulated genes. Dysregulation of ARPC1B expression has been detecteD in multiple human cancers and ARPC1B protein has been implicated in the control of actin polymerization. Moreover, ARPC1B is involved in many pathways such as cytoskeleton remodeling via actin; integrin mediated cell adhesion and movement of cell/subcellular compartments. The purpose of this research was to evaluate the expression levels of ARPC1B in different prostate cancer cell lines and investigate its potential role in disease progression. ARPC1B expression was analysed using western blot and qRT-PCR in multiple cell lines. We found ARPC1B protein and mRNA levels to be upregulated in the PC3 cell line compared to other cell lines. To validate the role of ARPC1B, siRNA was useD to knockdown ARPC1B in PC3 cells which resulteD in significant reduction of cell proliferation as measured using the MTS assay. Reduced cell growth and/or reduced migration in cells with ARPC1b knocked down was also seen using scratch assays. Tissue expression levels were also investigated II on a progression tissue microarray and showed increased intensity with disease progression from benign to localized cancer and castrate resistant disease. These data suggest that ARPC1B could be a valid prostate cancer marker. III Acknowledgements First and foremost, I would like to express my sincere gratitude to the Libyan Higher ministries of education & The University of Tripoli, who has given me the opportunity to continue with my education abroad. Beside the Ministries of education, I would like to express my sincere gratitude to my advisor Prof. Tarek Bismar for the continuous support of my master study and related research, for his patience, motivation, and immense knowledge. His guidance helped me in all the time of research and writing of this thesis. I would like to express my special thanks to Dr. Hatem Abou-Ouf for his valuable thoughts, advice and feedback. I would like to express my deepest gratitude to thank also my thesis committee members Dr. Bob Argiropoulos, Markus Eszlinger, Karl T. Riabowol, and Dr. Susan Lees-Miller who provided me an opportunity to join their team and gave me access to the laboratory and research facilities and for their valuable comments and insightful suggestions. Without their precious support, it would not be possible to conduct this research. I would like to express my deepest thanks to the Faculty of Medicine and the Department of Biochemistry and Molecular Biology at the University of Calgary for their help and support during these past few years, especially Dr. Sarah J. Childs, and Marion Mildenberger for their guidance and assistance throughout this program. Moreover, I am deeply thankful for all the members of Dr. Bismar’s laboratory; Dr. Ramy Sallam and Ms. chung-sze seck. IV Dedication: - In the end, I want to take the opportunity to extend my thanks to my beloved husband (Kamal Hrbeed) and my Parents Dr. Mohamed Zaaluk, and Karema, and my brother and sisters. Also, I would like to thank Dr. Ron Zellner, and Dr. Luana Zellner. Words cannot express how grateful I am to be part of my own family. Your prayer, support, and motivations were what sustained me thus far. I would also like to thank all of my friends who supported me to strive towards my goal. V TABLE OF CONTENTS CHAPTER 1 : - INTRODUCTION ............................................................................................ 1 BACKGROUND .............................................................................................................................. 1 1.1 Anatomy of the Prostate Gland ......................................................................................... 1 1.2 Prostate Pathology ............................................................................................................. 3 1.2.1 Benign prostatic hyperplasia (BPH) ........................................................................... 3 1.2.2 Prostatic Intraepithelial Neoplasia ............................................................................. 3 1.2.3 Prostate Cancer .......................................................................................................... 3 1.3 Epidemiology ..................................................................................................................... 4 1.4 Risk Factors ....................................................................................................................... 5 1.4.1 Endogenous Risk Factors ............................................................................................ 5 1.4.2 Exogenous Risk Factors ............................................................................................. 6 1.5 Progression of prostate cancer ........................................................................................... 6 1.6 Prostate Detection .............................................................................................................. 9 1.7 Biomarkers in prostate cancer: .......................................................................................... 9 1.8 ARPC1B .......................................................................................................................... 11 1.8.1 The role of ARPC1B in cancer ................................................................................. 17 HYPOTHESIS ............................................................................................................................... 19 OBJECTIVES ................................................................................................................................ 19 CHAPTER 2 : MATERIALS AND METHOD ........................................................................ 20 MATERIALS ................................................................................................................................ 20 2.1 Cell Lines ......................................................................................................................... 20 2.2 Cell culture ...................................................................................................................... 22 2.3 Antibodies ........................................................................................................................ 23 2.3.1 ARPC1B Antibody ................................................................................................... 23 2.3.2 GAPDH Antibody ..................................................................................................... 23 METHODS ................................................................................................................................... 25 2.4 Protein Extraction from Cell lines ................................................................................... 25 2.5 Western Blot .................................................................................................................... 25 2.6 RNA Extraction ............................................................................................................... 26 2.7 cDNA ............................................................................................................................... 27 2.8 Real-time reverse transcription – PCR ............................................................................ 27 2.9 Transfection and RNA Silencing ..................................................................................... 29 2.10 Proliferation Assay
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