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The Role of Semaphorin 5A in Pancreatic Cancer Progression and Metastasis

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The Role of Semaphorin 5A in Pancreatic Cancer Progression and Metastasis University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Spring 5-6-2017 The Role of Semaphorin 5A in Pancreatic Cancer Progression and Metastasis Sugandha Saxena Dr. University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Biochemistry Commons, and the Cancer Biology Commons Recommended Citation Saxena, Sugandha Dr., "The Role of Semaphorin 5A in Pancreatic Cancer Progression and Metastasis" (2017). Theses & Dissertations. 200. https://digitalcommons.unmc.edu/etd/200 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. THE ROLE OF SEMAPHORIN 5A IN PANCREATIC CANCER PROGRESSION AND METASTASIS By Sugandha Saxena A DISSERTATION Presented to the Faculty of The Graduate College of the University of Nebraska Medical Center In Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy Biochemistry and Molecular Biology Graduate Program Under the Supervision of Professor Rakesh K. Singh University of Nebraska Medical Center Omaha, Nebraska April 2017 Supervisory Committee Surinder K. Batra, Ph.D. Joyce Solheim, Ph.D. Micheal A. (Tony) Hollingsworth, Ph.D. Michel Ouellette, Ph.D. i THE ROLE OF SEMAPHORIN 5A IN PANCREATIC CANCER PROGRESSION AND METASTASIS Sugandha Saxena, Ph.D. University of Nebraska Medical Center Supervisor: Rakesh Singh, Ph.D. This dissertation investigates the pathological significance and functional role of Semaphorin 5A (SEMA5A), an axon guidance molecule, during Pancreatic Cancer (PC) progression and metastasis. We analyzed the expression of SEMA5A in human PC tissue and metastatic sites as well as in different PC progression models of Pancreatic Ductal Adenocarcinoma (PDAC) and Pancreatic Neuroendocrine Tumors (PanNET). This study has identified upregulation of SEMA5A in primary pancreatic tumors and metastases in comparison with the normal pancreas. Furthermore, we examined the functional role of SEMA5A and demonstrated that the upregulated secretory form of SEMA5A increases PC cell migration, as well as enhances metastasis by acting as a ligand for the Plexin B3 receptor. We have also shown that SEMA5A enhances PC cell migration by activating Met tyrosine kinase receptor. In addition, we made an attempt to understand the function of endogenous SEMA5A expression in a PC cell by generating knockdown of SEMA5A in different PC cell lines. Interestingly, we observed that loss of SEMA5A increases cellular migration and enhances metastasis by inducing Epithelial to Mesenchymal Transition (EMT). Furthermore, ii we demonstrate that upregulation of TGF2 secretion and non-canonical activation of PI3K-AKT signaling may mediate this transition. Similar to loss of SEMA5A, knockdown of Plexin B3 also induces a mesenchymal phenotype and enhances metastasis, though not by inducing EMT. Together, these data demonstrate that SEMA5A-Plexin B3 axis may play an important role in maintaining an epithelial state of PC cells that limits the invasive capabilities of the PC cell. Overall, the results presented in this dissertation reveal that SEMA5A signaling can mediate both tumor-promoting roles by enhancing cellular migration and angiogenesis and tumor inhibitory effects by maintaining the epithelial phenotype and keeping invasion under check. iii Table of Contents THE ROLE OF SEMAPHORIN 5A IN PANCREATIC CANCER PROGRESSION AND METASTASIS .............................................................................................. II TABLE OF CONTENTS ...................................................................................... IV LIST OF FIGURES .............................................................................................. XI LIST OF TABLES ............................................................................................. XV LIST OF ABBREVIATIONS: ............................................................................ XVI ACKNOWLEDGEMENTS ................................................................................ XIX CHAPTER 1: INTRODUCTION .............................................................................. 1 I. THE SIGNIFICANCE OF THE STUDY:..................................................................... 2 II. OVERVIEW OF THE NORMAL PANCREAS: ............................................................ 3 Anatomy: ....................................................................................................... 3 Histology: ....................................................................................................... 4 Function: ........................................................................................................ 4 III. PC: ............................................................................................................... 5 Epidemiology: ................................................................................................ 5 Risk Factors for PC Development: ................................................................ 6 Types of PC: .................................................................................................. 7 Difficulties in PC Therapy: ........................................................................... 10 Clinical Management of PC: ........................................................................ 11 Future Therapeutic Options: ........................................................................ 12 iv IV. METASTASIS: ............................................................................................... 13 Definition and Early Ideas: ........................................................................... 13 The Invasion-Metastatic Cascade: .............................................................. 14 Models of PC Metastasis: ............................................................................ 16 Targeting Metastasis: .................................................................................. 18 V. EPITHELIAL TO MESENCHYMAL TRANSITION (EMT): ......................................... 19 Types of EMTs: ........................................................................................... 21 EMT, MET, and Metastasis: ........................................................................ 21 Molecular Program of EMT: ......................................................................... 22 VI. SEMAPHORINS IN CANCER: ........................................................................... 24 Introduction and Classification: .................................................................... 24 Receptors for Semaphorins: ........................................................................ 25 Diverse Signaling of Semaphorins: ............................................................. 27 The Parallel Roles of Semaphorins in the Nervous System and Cancer Biology:........................................................................................................ 29 VII. CLASS 5 SEMAPHORINS: .............................................................................. 30 Structure: ..................................................................................................... 30 SEMA5A in Cancer: .................................................................................... 31 SEMA5A in PC: ........................................................................................... 32 Diverse Signaling of SEMA5A: .................................................................... 34 Putative Receptors of SEMA5A: .................................................................. 35 VIII. HYPOTHESIS AND SPECIFIC AIMS: ................................................................ 37 v CHAPTER 2: MATERIALS AND METHODS ..................................................... 51 I. HUMAN PC SPECIMENS: ................................................................................. 52 II. MOUSE MODEL OF PC DISEASE PROGRESSION SPECIMENS: ............................. 52 III. CELL LINE CULTURES AND TRANSFECTIONS:................................................... 52 Human Cell Lines: ....................................................................................... 52 Cloning of SEMA5A/Plexin B3 shRNA Oligos: ............................................ 53 Transfection of PC Cells: ............................................................................. 53 IV. ANIMAL MODELS AND DETAILS OF IN VIVO STUDIES: ........................................ 54 Study Approval: ........................................................................................... 54 Xenogenic Mouse Models: .......................................................................... 54 V. GENE EXPRESSION ANALYSIS: ....................................................................... 56 RNA Isolation: ............................................................................................. 56 Reverse Transcription: ................................................................................ 57 Quantitative Real-Time PCR (qRT-PCR): ................................................... 57 VI. PROTEIN ANALYSIS: ...................................................................................... 58 Protein Isolation, Quantification, and Immunoblotting: ...............................
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