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The Function of Erbin, a Scaffold Protein, As a Tumor Suppressor in Colon Cancer

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The Function of Erbin, a Scaffold Protein, As a Tumor Suppressor in Colon Cancer University of Kentucky UKnowledge Theses and Dissertations--Molecular and Cellular Biochemistry Molecular and Cellular Biochemistry 2018 THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER Payton D. Stevens University of Kentucky, [email protected] Digital Object Identifier: https://doi.org/10.13023/ETD.2018.038 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Stevens, Payton D., "THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER" (2018). Theses and Dissertations--Molecular and Cellular Biochemistry. 36. https://uknowledge.uky.edu/biochem_etds/36 This Doctoral Dissertation is brought to you for free and open access by the Molecular and Cellular Biochemistry at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Molecular and Cellular Biochemistry by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Payton D. Stevens, Student Dr. Tianyan Gao, Major Professor Dr. Trevor Creamer, Director of Graduate Studies THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER ____________________________________ DISSERTATION ____________________________________ A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Medicine at the University of Kentucky By Payton Drew Stevens Lexington, Kentucky Director: Dr. Tianyan Gao, Professor of Molecular and Cellular Biochemistry Lexington, Kentucky 2017 Copyright © Payton D. Stevens 2017 ABSTRACT OF DISSERTATION THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that play important roles in orchestrating cell signaling. Here, we show that Erbin functions as a tumor suppressor in colon cancer. Analysis of Erbin expression in patient specimens reveals that Erbin is downregulated at both mRNA and protein levels in tumor tissues. Functionally, knockdown of Erbin disrupts epithelial cell polarity and increases cell proliferation in 3D culture. In addition, silencing Erbin results in an increase in the amplitude and duration of signaling through Akt and RAS/RAF pathways. Moreover, Erbin-loss induces epithelial-mesenchymal transition (EMT), which coincides with a significant increase in cell migration and invasion. Erbin interacts with KSR1 and displaces it from the RAF/MEK/ERK complex to prevent signaling propagation. Furthermore, genetic deletion of Erbin in Apc knockout mice promotes tumorigenesis and significantly reduces survival. Tumor organoids derived from Erbin/Apc double knockout mice have increased tumor initiation potential along with increased Wnt target gene expression as seen by qPCR. Collectively, the studies within this dissertation identify Erbin as a negative regulator of EMT and tumor progression by directly suppressing Akt and RAS/RAF signaling in vivo. KEYWORDS: Polarity, EMT, Cell Motility, ERK signaling, Scaffold protein, and Tumor Suppressor Payton D. Stevens December 15, 2017 THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER By Payton Drew Stevens Tianyan Gao, Ph.D. Director of Dissertation Trevor Creamer, Ph.D. Director of Graduate Studies December 15, 2017 For my family. ACKNOWLEDGEMENTS First and foremost, I must acknowledge and thank Dr. Tianyan Gao. This work truly would not have been possible if not for her support. Through my time as a laboratory technician she encouraged me to return to school and pursue my dreams of gaining a Ph.D. During my time as a graduate student she has worked with me and pushed me to expand my knowledge in the cancer research field. I know that the skills and knowledge that I have acquired while working with her will allow me to successfully continue on my career path. Dr. Gao has undoubtedly been one of the most influential mentors in my life and I couldn’t be more thankful that I was able to work and study in her laboratory for the last eight years. Thank you to the many other members and past members of the Gao laboratory. Especially I would like to say thank you to Dr. Yang-An Wen and Dr. Xiaopeng Xiong for their comradery and sharing their technical expertise with me. I believe the collegial atmosphere of our lab has made my time as a graduate student as enjoyable as possible. I would like to thank the members of my committee for their support and guidance over the last several years. I appreciate the time you have spent and the advice that you have provided in order to shape my dissertation project. Also, thank you to Dr. Val Adams for kindly taking the time to act as my outside examiner. Also, I would like to thank the Markey Cancer Center and Department of Molecular and Cellular Biochemistry. I have received boundless support from members of the Cancer Center and Biochemistry department. I know that I am a better scientist today and more prepared for my future endeavors from my time spent working with each of these groups. iii Lastly, I absolutely have to thank my family and friends. I have to recognize that my parents have supported me unconditionally throughout my life and have always encouraged me to pursue my dreams. Without a doubt, my pursuit of this degree would not have been possible without them. A very special thank you is due to my fiancée, Dr. Brittany Carpenter, for always providing support and assistance during the past few years, inside the laboratory and out. And thank you to my friends for your support and companionship through the years. iv TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................ iii TABLE OF CONTENTS ................................................................................................. v LIST OF FIGURES ....................................................................................................... viii CHAPTER 1: INTRODUCTION .................................................................................... 1 1.1 Signaling Activation in Colorectal Cancer .............................................................. 1 1.2 The Role of Scaffold Proteins in Signal Transduction........................................... 14 1.3 Erbin Distribution and Function in Epithelial Tissues ........................................... 17 1.4 The Role of Erbin in Cancer .................................................................................. 28 1.5 Goals and Hypothesis for Dissertation ................................................................... 33 CHAPTER 2: MATERIALS AND METHODS .......................................................... 35 2.1 Cell Lines and Cell Culturing ................................................................................ 35 2.2 Gene Knockdown by shRNA ................................................................................. 36 2.3 Cell Growth Assay ................................................................................................. 36 2.4 RNA Extraction and QPCR ................................................................................... 37 2.5 Transwell Migration and Invasion Assay .............................................................. 37 2.6 Drug Treatment ...................................................................................................... 38 2.7 Single Cell Motility Assay ..................................................................................... 38 2.8 Western Blotting Analysis ..................................................................................... 39 2.9 2-D Immunofluorescent Staining ........................................................................... 39 2.10 3-D Immunofluorescent Staining ......................................................................... 40 2.11 Histologic analysis and immunohistochemical (IHC) staining ...........................
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