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Evidence of Y Chromosome Long Non-Coding Rnas Involved in the Radiation Response of Male Non-Small Cell Lung Cancer Cells

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Evidence of Y Chromosome Long Non-Coding Rnas Involved in the Radiation Response of Male Non-Small Cell Lung Cancer Cells Graduate Theses, Dissertations, and Problem Reports 2020 Evidence of Y Chromosome Long Non-Coding RNAs involved in the Radiation Response of Male Non-Small Cell Lung Cancer Cells Tayvia Brownmiller West Virginia University, [email protected] Follow this and additional works at: https://researchrepository.wvu.edu/etd Part of the Cancer Biology Commons, Cell Biology Commons, Genetics Commons, Molecular Genetics Commons, and the Radiation Medicine Commons Recommended Citation Brownmiller, Tayvia, "Evidence of Y Chromosome Long Non-Coding RNAs involved in the Radiation Response of Male Non-Small Cell Lung Cancer Cells" (2020). Graduate Theses, Dissertations, and Problem Reports. 7784. https://researchrepository.wvu.edu/etd/7784 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. Evidence of Y Chromosome Long Non-Coding RNAs involved in the Radiation Response of Male Non-Small Cell Lung Cancer Cells Tayvia Brownmiller Dissertation submitted to the West Virginia University School of Medicine at West Virginia University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Cancer Cell Biology Elena Pugacheva, PhD, Chair Linda Vona-Davis, PhD Heath Damron, PhD Erik Bey, PhD Scott Weed, PhD Ivan Martinez, PhD, Mentor Graduate Program in Cancer Cell Biology Morgantown, West Virginia 2020 Keywords: Long non-coding RNA, lncRNA, non-small cell lung cancer, NSCLC, radiation, radiosensitivity, radioresistance, Y chromosome, linc-SPRY3 Copyright 2020 Tayvia Brownmiller ABSTRACT Evidence of Y Chromosome Long Non-Coding RNAs involved in the Radiation Response of Male Non-Small Cell Lung Cancer Cells Tayvia Brownmiller Non-small cell lung cancer (NSCLC) is the number one cause of cancer related mortality in the United States and worldwide. Advanced and therapeutically resistant lung tumors contribute to the high rate of mortality from NSCLC, therefore there is a need for new methods of diagnosing and treating this disease. Long non-coding RNAs (lncRNAs) have been shown to be a crucial component of human molecular biology, regulating nearly every cellular pathway from chromatin condensation to transcription and translation. Furthermore, many lncRNAs have been classified as oncogenes or tumor suppressors, highlighting the various molecular mechanisms they are involved in regarding the formation and progression of cancer and their use as prognostic and diagnostic biomarkers has been proposed in numerous cancers, including NSCLC. Our group has discovered, for the first time, a three member family of Y chromosome lncRNAs (linc-SPRY3-2, lin-SPRY3-3, and linc-SPRY3-4) which regulate NSCLC cell response to ionizing radiation (IR). Briefly, the linc-SPRY3 family demonstrated a dose dependent induction of expression following exposure to IR in male radiosensitive NSCLC cell lines, but not in male radioresistant cell lines. This difference was revealed to be due to loss of the Y chromosome in the radioresistant cell lines. Using gain-of-function and loss-of-function experiments, we demonstrated statistically significant changes in cell viability and apoptosis in vitro. Furthermore, in vivo tumor growth delay assays showed a more radioresistant phenotype in tumors with knockdown of the linc-SPRY3 RNAs versus control tumors. We hypothesize linc- SPRY3-2/3/4 mediate their tumor suppressive effect via sequestration of the RNA binding protein IGF2BP3 demonstrated by CLIP and RNA degradation assays. Moreover, DNA FISH and bioinformatic analysis revealed a trending negative correlation in patient survival between loss of the Y chromosome and linc-SPRY3-2/3/4. These findings suggest that the linc-SPRY3 RNAs function as tumor suppressors by promoting cell death following IR through interactions with IGF2BP3, and could have potential as biomarkers in male NSCLC. Acknowledgements The work presented in this dissertation is the culmination of seven years of blood, sweat and many many many tears, and would not have been possible without the support of a number of individuals. First and foremost, I need to thank my mentor, Dr. Ivan Martinez. Though there have been numerous times where I was frustrated beyond belief with both you and/or the research, this would not have been possible without your guidance. This was a learning curve for the both of us, which we have both admitted multiple times throughout this process, and I wholeheartedly believe we are both the better for it. Your unbelievable mentorship has prepared me for whatever comes next and I hope one day I get the chance to do for others what you have done for me. I also have to thank my graduate program and my committee members. Without you, this milestone could not have been realized. Thank you all for your generosity, support and guidance. I would not be the scientist or person I am today without you. Next, I have to thank three amazing women I had the privilege to work with. The three of you went from coworkers, to friends and now I consider you family because only family could have put up with me and my craziness for so long! Karen, Jamie, and Abby, I would not have survived this without your continual support, even after you all moved on. Karen, I will miss your birthday cakes and pies and the sage advice you always had on hand no matter what the situation. Jamie, I can’t thank you enough for showing me what true vigilance looks like. Even though most of the time you could not stand to be at the bench, you pushed through and eventually found something you love doing and its always something I will admire about you. You are both amazing women, mentors, and even more amazing friends and I will never be able to fully thank you for everything you have given me. Abby, you were my first real test as a mentor and I could not be prouder of what you have done since leaving the lab. I wasn’t sure I would be cut out for the job, but thanks to you I found a passion for mentoring and learned so much from you and about myself and for that I will be eternally grateful. Even more so, I am grateful for our friendship. From the moment I pointed out your insulin pump tubing, I knew you would become a lifelong friend and I look forward to seeing what’s next for you! I also have to thank the many other members of the Martinez Lab, past and present. Aly, you are going to do great things and I can’t wait to see what the next chapter of your life holds for you. Thank you for allowing me to be part of your journey here at WVU. To all of the other undergraduates (there are too many to name them all) who I have the chance to work with, thank you for helping me become a better mentor and good luck with your futures! To Brandon, though your time in our lab was short, I have to say thank you for coming in and hitting the ground running like you did. I was at my wits end when you joined the lab and without your help and friendship, I don’t think I would have made it. To Emily, Michael, and Alana, in the brief time I have spent with y’all, I can see that the Martinez Lab is in good hands. You are all amazing and I wish you the best of luck in whatever that comes next. I next would like to thank my friends, who have done so much to help keep me sane throughout all of this grad school mess. Dudley, you were my very first friend here and have always been there for me when I needed someone. I can’t tell you how much your friendship has meant to me. iii One of my most treasured grad school memories will be that camping trip you organized. Even though it did not start off well or go the way we planned at all that weekend, it was still one of the best times I’ve had during my time here. Abi, from the moment we bonded over Harry Potter at our interview weekend, I knew you and I would be friends for life and I can’t imagine it any other way. You made grad school so much more fun and I couldn’t have survived it without you. I would also like to take this opportunity to formally apologize for spoiling that one episode of Buffy for you back in first year, and to tell you that I am now much more careful when discussing TV and movies with others. To Sarah, oh how I will miss our impromptu hallway conversations about all things MARVEL or obscure sci-fi, or the times we plan to hang out and binge a show on Netflix only to spend the evening ranting about school, family or whatever else is happening in our lives. You’ve truly made these last few years of grad school much more bearable. To my high school best friend Emily, though we were a thousand miles apart, you were always there when I needed someone to vent to and blindly take my side no matter what.
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