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The Role of TGFβ Type III Receptor in Lung Cancer Cell Migration And Western University Scholarship@Western Electronic Thesis and Dissertation Repository 6-26-2018 1:00 PM The role of TGFβ type III receptor in lung cancer cell migration and invasion Anthony Ziccarelli The University of Western Ontario Supervisor Di Guglielmo, John The University of Western Ontario Graduate Program in Physiology and Pharmacology A thesis submitted in partial fulfillment of the equirr ements for the degree in Master of Science © Anthony Ziccarelli 2018 Follow this and additional works at: https://ir.lib.uwo.ca/etd Recommended Citation Ziccarelli, Anthony, "The role of TGFβ type III receptor in lung cancer cell migration and invasion" (2018). Electronic Thesis and Dissertation Repository. 5454. https://ir.lib.uwo.ca/etd/5454 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. i Abstract Metastasis is responsible for 90% of cancer-related deaths. An important early step in the metastatic process is epithelial-to-mesenchymal transition (EMT) of tumor cells. Stimulated by TGFβ signaling, cells that undergo EMT have increased migratory and invasive potential, resulting in metastasis and the development of tumors at a secondary site. The TGFβ type 3 receptor (TβR3) has been implicated in modulating TGFβ signaling, yet its functional outcomes remain unclear. My findings demonstrated that TβR3 silencing does not alter TGFβ-dependent Smad2 phosphorylation in neither H1299, not A549 non- small cell lung carcinoma cells but reduces Smad2 expression in H1299 cells. Interestingly, although TβR3 knockdown did not alter mRNA expression of EMT markers, it resulted in the reduction of TGFβ-dependent EMT protein markers. Finally, inhibition of EMT attenuated cellular invasion while enhancing chemotactic migration. Together, these results suggest that TβR3 has a distinct role in modulating EMT and cellular motility in a Smad-independent manner. Keywords Transforming growth factor beta (TGFβ), Smad signaling, transforming growth factor beta type III receptor (TβR3), betaglycan, epithelial-to-mesenchymal transition (EMT), migration, invasion ii Co-Authorship Statement All experiments were conducted and analyzed by Anthony Ziccarelli. For the microarray analysis, RNA was extracted by Anthony Ziccarelli, processed and loaded onto Affymetrix Human GeneChip 2.0 by David Carter (London Regional Genomics Center), and analyzed by Anthony Ziccarelli. iii Acknowledgments Firstly, I’d like to thank Dr. John Di Guglielmo for taking me on as a student on short notice and putting great faith in me right from the start of my project. Your constant positivity, optimism, and encouragement helped me get through those tough times when experiments weren’t progressing as smoothly as I hoped. Trusting my independence, while addressing any question, comment, or concern I had, allowed me to think critically and come up with solutions on my own. You welcomed me into your lab with open arms and made every day enjoyable. Your Netflix recommendations, Bill Burr jokes, and interesting facts kept the mood around the lab fun and light. Thank you for welcoming us into your home for holiday dinners, while celebrating our birthdays and accomplishments with lunches, donuts, and snacks. These subtleties made the lab feel much less like a work environment, and much more like a family. Also, thank you for letting me act as a teaching assistant in my first semester, even though there was a lot on my research plate to learn. It helped me appreciate the intricacies and effort that goes into undergraduate courses. Thank you to my advisory committee members – Dr. Peter Chidiac, Dr. Lina Dagnino, and Dr. Ruud Veldhuizen – for your advice and suggestions. Your tough questions during our meetings have compelled me to think critically when developing experiments and analyzing data, allowing me to become a better researcher. I want to thank Dr. Nicole Campbell and Dr. Sarah McLean for giving me the opportunity to develop my teaching skills through TAing your IMS lab courses. As a graduate from that program, it was an incredible feeling to give back to the program that helped me get to where I am now. Also, teaching students how to perform techniques that I perform daily forced me to know them inside and out, which helped troubleshooting whenever I had technical issues in my own experiments. To my fellow grad students, Charles, Eddie, Sam, and Evelyn. Thanks for teaching me how to perform the techniques I needed to conduct my research, and for showing me the ropes on the entire graduate school process. I can only imagine how difficult it would’ve been to figure everything out on my own. Having you around while we were going through similar iv difficulties really helped convince me there was a light at the end of the tunnel. I’m confident your advice regarding what to do, and what not to do, saved me from many headaches. I know how tough presentations can be, but thanks for allowing me to sit in on your talks. It always gave me thoughts and ideas that I could incorporate into my own presentations. Many apologies for not giving in to your attempts at making me more cultured. A big thank you to Colleen and Craig for helping with any reagent, kit, or piece of equipment that I was having trouble with. All your experimental tips and tricks made my research more clear, complete, and successful. Thanks for letting me pick your brain and lean on you for wisdom whenever I hit roadblocks in my research or my life, it’s really meant a lot. Get ready for a Leafs/Oilers 2019 Stanley Cup Final, Craig. To my roommates, friends from the Soo, and friends from school: I know I can be irritable sometimes, especially when stressed, but I’m thankful you understood and put up with me. You collectively helped me overcome pessimism, frustration, and a lack of confidence when times were tough. Despite my hesitation, your convincing me to take breaks and enjoy myself helped maintain a work-life balance and kept me sane. The sports, concerts, board game nights, and day trips always put a smile on my face and gave my brain a rest. With all the ups and downs, the last two years have been some of the best of my life. Finally, thank you to my family for the unending support over the years. Being so far from home hasn’t been easy, but no matter how short or infrequent my visits were, every day was special (except that time I crushed my hand). Even though none of you are scientists, you’ve done your best to try and understand what I’ve been doing for the last two years. The next 100 or so pages are dedicated to you. v Table of Contents Abstract ................................................................................................................................ i Co-Authorship Statement.................................................................................................... ii Acknowledgments.............................................................................................................. iii Table of Contents ................................................................................................................ v List of Tables ................................................................................................................... viii List of Figures .................................................................................................................... ix Abbreviations List .............................................................................................................. xi Chapter 1: Introduction ................................................................................................... 1 1.1 Lung Cancer ................................................................................................................. 1 1.1.1 Disease Process ..................................................................................................... 1 1.1.2 Lung Cancer Metastasis ........................................................................................ 2 1.1.3 Epithelial to Mesenchymal Transition and Metastasis.......................................... 3 1.2 TGFβ Signaling ............................................................................................................. 7 1.2.1 TGFβ in Cancer ..................................................................................................... 7 1.2.2 TGFβ Family of Ligands and Receptors ............................................................... 7 1.2.3 SMAD Function and Regulation ......................................................................... 11 1.2.4 Canonical and Non-Canonical TGFβ Signaling ................................................ 13 1.2.5 Regulation of EMT ............................................................................................. 17 1.2.6 TGFβ, EMT, and Autophagy .............................................................................. 19 1.2.7 Matrix Metalloproteinases .................................................................................. 21 1.3 Transforming Growth Factor β Type 3 Receptor ....................................................... 23 1.3.1 TβR3 in Cancer ................................................................................................... 23 1.3.2 Structure of TβR3 ...............................................................................................
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