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The Functional Role of Mir-210 in Hypoxia-Induced

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The Functional Role of Mir-210 in Hypoxia-Induced THE FUNCTIONAL ROLE OF MIR-210 IN HYPOXIA-INDUCED ANGIOGENESIS A DISSERTATION SUBMITTED TO THE FACULTY OF THE UNIVERSITY OF MINNESOTA BY ERICA K. SCHNETTLER IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY ADVISOR: SUNDARAM RAMAKRISHNAN FEBRUARY 2017 © ERICA K. SCHNETTLER 2017 Acknowledgements Foremost, I would like to express my sincere gratitude to my advisor, Dr. Sundaram Ramakrishnan, for his thoughtfulness and support over the last four and a half years. He is truly an inspiring teacher, academic, and research scientist. I am fortunate to have been trained under his guidance and care. I could always count on Ramki to be there when I ran into problems and he always pushed me to always question and explore further. He has absolutely transformed the way I think as a scientist. I will miss his friendly smile and constant optimism! I am also very grateful to the many members of our lab that have come and gone over the years. I especially thank Dr. Colleen Rivard and Dr. MiHae Song for teaching me the medical side of gynecologic oncology and for connecting me to the importance of patient driven research. I also thank Dr. Manju Saluja, Dr. Devika Kir, and Annaporna Venkatachalam for their helpful advice, constructive criticism, openness, and companionship during my years in the Ramki lab. I additionally thank our many interns and summer students for helping me to discover my love for teaching. For their significant contributions to my thesis work, I thank Dr. Goutam Ghosh – FGFRL1-Luc constructs, Dr. Yan Zeng – miR-210 knock-out mice, and Dr. Alexey Benumov – zebrafish work. I would also like to thank my committee members: Dr. Timothy Walseth, Dr. Jill Siegfried, Dr. Cheuk Leung, Dr. Kaylee Schwertfeger, and Dr. Subree Subramanian, for their suggestions and thoughtful advice during my graduate career. Finally, I am very glad to have been supported by the PharmacoNeuroImmunology (PNI) training grant, and thank Dr. Sabita Roy, Dr. Thomas Molitor, and Yorie Smart for their funding and guidance. i I dedicate this work to my parents. ii Abstract MicroRNAs (miRNA) are involved in fine-tuning cellular responses to hypoxia. miR-210, a hypoxia-induced miRNA, has been shown to play an important role in angiogenesis. miR-210 is known to target key players in mitochondrial metabolism, DNA repair, cell cycle regulation, and cell survival. Such targets may broadly affect endothelial cell homeostasis and angiogenesis. One of the highly ranked targets of miR-210 is fibroblast growth factor receptor-like protein 1 (FGFRL1). We confirmed this by luciferase reporter assays that demonstrated FGFRL1 is a direct target of miR-210. Although FGFRL1 binds Fibroblast Growth Factor (FGF) ligands, it is not a typical FGF receptor because it lacks an intracellular receptor tyrosine kinase domain. In the present study, we investigated the role of FGFRL1, on regulating bFGF signaling in endothelial cells. Our studies suggest that during hypoxia miR-210 inhibits FGFLR1, a dominant negative or “decoy” receptor, leading to increased FGF signaling in endothelial cells. We show that transfection with either miR-210 duplex or FGFRL1 siRNA can sensitize human umbilical vein endothelial cells (HUVECs) to bFGF induced proliferation. Cells treated with miR-210 or siFGFRL1 also show increased fibroblast growth factor receptor- 1 (FGFR-1), Protein Kinase B (AKT) and Mitogen-activated protein kinase (MAPK) phosphorylation after treatment with bFGF. To corroborate our in vitro finding in endothelial cells, we next investigated the role of miR-210 and FGFRL1 on angiogenesis using in vivo models. In a transgenic zebra fish model, we found that injection of miR-210 caused a 30% increase in angiogenesis at the caudal vein plexus after 36-hours. Injection of FGFRL1 siRNA showed similar results and increased angiogenesis compared to control. miR-210 knock- iii out (KO) mice were subsequently generated to further understand the role of miR-210 on angiogenesis. Interestingly, miR-210 KO mice showed increased the levels of FGFRL1 in mouse endothelial cells and other tissues, further demonstrating that miR- 210 can regulate FGFRL1 levels in vivo. In the matrigel plug assays, miR-210 KO mice showed decreased angiogenesis in the presence of bFGF compared to wild-type (WT) mice. In the aortic ring assays, miR-210 KO aortas showed decreased vessel sprouting in the presence of FGF and hypoxia compared to WT. In a subcutaneous tumor model, miR-210 KO mouse also showed decreased vascular recruitment to the tumor compared to WT mice. Overall, our in vivo experiments show that miR-210 plays a critical role regulating in pathological angiogenesis. Together these findings provide insight that miR-210 sensitizes endothelial cells to bFGF signaling by targeting the dominant- negative receptor, FGFRL1, during hypoxia. Furthermore, modulation of miR-210 or FGFRL1 expression or activity is a viable strategy to regulate angiogenesis, either positively during ischemia or negatively during cancer progression and metastasis. iv Table of Contents Acknowledgements .......................................................................................................i Dedication ......................................................................................................................ii Abstract .........................................................................................................................iii Table of Contents ..........................................................................................................v List of Figures .............................................................................................................viii List of Tables .................................................................................................................x Abbreviations ................................................................................................................xi Chapter I: Background ......................................................................................1 Tumor Microenvironment ........................................................................................2 What is the tumor microenvironment? ..............................................................................2 Key cellular components ...................................................................................................3 Role in drug resistance .......................................................................................6 Therapeutics targeting the tumor microenvironment ........................................................6 Hypoxia ....................................................................................................................8 What is hypoxia? .............................................................................................................8 The role of hypoxia inducible factor 1 .............................................................................9 Tumor hypoxia ................................................................................................................12 Angiogenesis .........................................................................................................16 Mechanisms of angiogenesis ..........................................................................................16 Angiogenesis in cancer ..................................................................................................20 Antiangiogenic therapies .........................................................................................22 Fibroblast Growth Factor Signaling ………......……………………………….…….24 Key cellular components .................................................................................................24 Molecular pathways ........................................................................................................27 Role in Angiogenesis ……………....................……………………..............…...……….28 MicroRNA ...............................................................................................................30 miRNA synthesis ……………............……....…………….............…....…………………....30 Mechanism of action ……………………............…………………..............………...…......31 miRNAs in cancer and angiogenesis ……......…........…...…...…....................…......33 Aims of Research .................................................................................................36 Chapter II: miR-210 modulates bFGF signaling and angiogenesis by downregulating FGFRL1 in hypoxic endothelial cells .................................39 v Introduction ............................................................................................................40 Materials & Methods ..............................................................................................43 Cell culture & hypoxia .....................................................................................................43 Reagents .........................................................................................................................43 Real-time PCR ……………....………………...….............…….............…..…...……....…..44 Primers ………………………………………………………....…………..............................44 miR-210 overexpression & siRNA knockdown …...………....……............…...................45 Luciferase assay ……………………………….............……....……....…...............…….....45 Cell viability ………....………………………………….............…....……................……….45 Real-time
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