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The Regulations of Mir-30C-3-3P and Its Antitumor Mechanism in Ovarian

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The Regulations of Mir-30C-3-3P and Its Antitumor Mechanism in Ovarian THE REGULATIONS OF MIR-30C-3-3P AND ITS ANTITUMOR MECHANISM IN OVARIAN CANCER by HA THU NGUYEN (Under the Direction of Dr. Mandi Murph) ABSTRACT Lysophasphatidic acid (LPA) is a mitogenic phospholipid present within the ovarian tumor microenvironment that induces ovarian cancer progression through multiple intracellular signaling cascades, leading to cell growth, motility and proliferation. MicroRNAs (miRNAs) are small, non-protein-coding entities with important roles in post- transcriptional regulation of most of the human genome. Previously, we found that the expression of miR-30c-2-3p is induced by LPA and has an important role in the regulation of cell proliferation in ovarian cancer cells. The goals of this study were to examine the correlation between LPA and miR-30c-2-3p expression as well as mechanisms of miR-30c- 2-3p antitumor effects. We observed that Dicer and epigenetic modifications, particularly DNA methylation and histone methylation, were not the major regulators of miR-30c-2-3p overexpression. Applying a combination of bioinformatics, qRT-PCR, immunoblotting and luciferase assays, we uncovered a regulatory pathway between miR-30c-2-3p and the expression of the transcription factor, ATF3. LPA triggers the expression of both miR-30c- 2-3p and ATF3 in SKOV-3 and OVCAR-3 serous ovarian cancer cells. The 3´-untranslated region (3´-UTR) of ATF3 was a predicted, putative target for miR-30c-2-3p, which we confirmed as a bona-fide interaction using a luciferase reporter assay. Furthermore, the presence of anti-miR-30c-2-3p enhanced ATF3 mRNA and protein after LPA stimulation. Thus, the data suggest that after the expression of ATF3 and miR-30c-2-3p are elicited by LPA, subsequently miR-30c-2-3p negatively regulates the expression of ATF3 through post- transcriptional silencing, which prevents further ATF3-related outcomes as a consequence of LPA signaling. Our in vivo pilot study shows evidence that miR-30c-2-3p can be a potential therapy for ovarian cancer. To date, there is limited information on miRNA mechanisms associated with LPA. Thus our findings bring in more understanding about the signaling circuits initiated by LPA, especially at the level of post-transcriptional silencing regulated by miRNAs. Furthermore, we provide experimental data to support the regulation of ATF3, another gene transcript targeted via miR-30c-2-3p, extending the current list, which includes BCL-9, HIF2A, X-box binding protein 1, Cyclin E1 and an adaptor protein of the NF-κB signaling pathway. INDEX WORDS: Ovarian cancer, MicroRNAs, miR-30c-2-3p, Lysophosphatidic acid (LPA), Activating Transcription Factor 3 (ATF3). © 2015 Ha Thu Nguyen All Rights Reserved THE REGULATIONS OF MIR-30C-3-3P AND ITS ANTITUMOR MECHANISM IN OVARIAN CANCER by HA THU NGUYEN Pharm.D., Hanoi University of Pharmacy, Vietnam, 2005 M.P.H., Emory University, 2009 A Dissertation Submitted to the Graduate Faculty of The University of Georgia in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY ATHENS, GEORGIA 2015 THE REGULATIONS OF MIR-30C-3-3P AND ITS ANTITUMOR MECHANISM IN OVARIAN CANCER by HA THU NGUYEN Major Professor: Mandi Murph Committee: Michael Bartlett Eileen Kennedy Nancy Manley Jianfu (Jeff) Chen Electronic Version Approved: Suzanne Barbour Dean of the Graduate School The University of Georgia December 2015 DEDICATION To my son, Tiger, thank you for your unconditional love. This work is for, and because of you. To my loving husband, Jeff, for always being supportive. To my parents, who encouraged me to see the world for myself and to explore all aspects of my life. To Dr. Yunzhi Li, who taught me how to balance between both professional and motherly roles. Your endless support has given me precious time to finish this research. To my big brother, big sister and younger brother: you always stand by my side. iv ACKNOWLEDMENTS I would like to express my gratitude to my advisor, Dr. Mandi Murph, for offering me an opportunity to conduct this research in her lab. I am truly grateful for her expertise, her patience and the awesome research atmosphere she provided in the lab. Working under her direction was one of the most important and informative experiences in my life. I deeply appreciate the other members of my committee, Dr. Michael Bartlett, Dr. Eileen Kennedy, Dr. Nancy Manley and Dr. Jeff Chen, for their insightful comments and encouragement, which motivated me to widen my research from various perspectives. My special thanks goes to Dr. Bartlett for continuously supporting me ever since I was admitted to UGA and for helping me improve my writing, as well as for advising me on my career. I appreciate Dr. Kennedy for her technical and others warm-hearted advices. Thanks to Dr. Manley for joining my committee at a very late time and providing scientific insight into my research. Thanks to Dr. Chen for his always-optimistic stance and his confidence in my research. My sincere thanks goes to Dr. Aaron Beedle, who helped me with troubleshooting experiments and who generously gave me access to the equipment in her lab. I also thank Dr. Robert Arnold and Dr. Brian Cummings for their help during the early years of my research. v I would like to say to Dr. Shelley Hooks, during the hard time, your kindness meant so much. Furthermore, I am pleased to tell my lab mates and friends, Molly Altman, Wei Jia, Ali Alshamrani and Sudeepti Kuppa, I enjoyed working with you guys. Finally, I want to express my gratitude to the Department of Pharmaceutical and Biomedical Sciences, the College of Pharmacy and the University of Georgia for their generous financial support. vi TABLE OF CONTENTS Page DEDICATION .............................................................................................................................................. iv ACKNOWLEDGEMENTS .......................................................................................................................... v TABLE OF CONTENTS ........................................................................................................................... vii LIST OF TABLES ....................................................................................................................................... ix LIST OF FIGURES ....................................................................................................................................... x CHAPTER 1. INTRODUCTION AND LITERATURE REVIEW ............................................................................... 1 2. DICER AND MICRORNAS: ONCOMIRS ARE THE NEXT FRONTIER OF ONCOGENES AFFECTING CANCER ETIOLOGY AND TUMOR PROGRESSION ........................................... 32 3. MIR-30C-2-3P AND DICER IN OVARIAN CANCER ..................................................................... 58 4. MOLECULAR EPIGENETICS IN THE MANAGEMENT OF OVARIAN CANCER: ARE WE INVESTIGATING A RATIONAL CLINICAL PROMISE? ............................................. 70 5. EPIGENETIC REGULATION OF MIR-30C-2-5P ............................................................................ 95 6. LYSOPHOSPHATIDIC ACID MEDIATES ACTIVATING TRANSCRIPTION FACTOR 3 EXPRESSION WHICH IS A TARGET FOR POST-TRANSCRIPTIONAL SILENCING BY MIR-30C-2-3P .......................................................................................................... 107 7. CONCLUSION .......................................................................................................................................... 130 REFERENCES ........................................................................................................................................................ 139 vii Page APPENDICES ......................................................................................................................................................... 196 A. MIRNA-30C-2-3P AND OVARIAN CANCER ............................................................................... 196 B. ADDITIONAL DATA OF ATF3 .......................................................................................................... 216 C. SUPPRESSION OF THE GTPASE-ACTIVATING PROTEIN RGS10 INCREASES RHEB-GTP AND MTOR SIGNALING IN OVARIAN CANCER CELLS .................................. 222 D. VINYL SULPHONE ANALOGS OF LYSOPHOSPHATIDYLCHOLINE IRREVERSIBLY INHIBIT AUTOTAXIN AND PREVENT ANGIOGENESIS IN MELANOMA........................ 228 viii LIST OF TABLES Page Table 1.1 LPA receptors and their roles in cancer ..................................................................................... 4 Table 1.2 Differences in molecular alterations between low-grade and high-grade ovarian cancer ............................................................................................................. 14 Table 1.3 Dichotomous roles of ATF3 in cancer ....................................................................................... 21 Table 2.1 miRNAs associated with cancer and their known targets ................................................ 45 Table 2.2 DICER alterations in cancers ......................................................................................................... 54 Table 3.1 Absolute Ct values of LPA receptor 1-5 expression in ovarian cancer cells SKOV-3 ........................................................................................................................... 63 Table 4.1 Alterations in multiple miRNAs among ovarian cancer .................................................... 78 Table 4.2 Epigenetic drugs in gynecological cancer
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