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Microrna Regulation of CD44 and CD151 in Hepatocellular Carcinoma

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Microrna Regulation of CD44 and CD151 in Hepatocellular Carcinoma microRNA regulation of CD44 and CD151 in hepatocellular carcinoma: Implications for novel therapies Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Ji Hye Kim, M.S. Graduate Program in Pharmacy The Ohio State University 2015 Dissertation Committee: Thomas D. Schmittgen, PhD, Advisor Jack C. Yalowich, PhD Mitch Phelps, PhD Copyright by Ji Hye Kim 2015 ABSTRACT Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, accounting for an estimated 745,000 deaths per year, representing 10% of all deaths from cancer. Most patients present with advanced HCC for which the overall survival is poor due to rapid tumor progression, metastasis and lack of effective treatments. Sorafenib is the first-line treatment for the advanced HCC, however sorafenib treatment showed clinically modest improvement and a number of patients develop resistance to sorafenib. There exists an urgent need to better understand the molecular mechanisms of the development of HCC and the resistance to current therapy and to develop new therapeutic options for advanced or recurrent HCC. We confirm previous findings that low miR-199a-3p expression is correlated with poor survival in HCC and that miR-199a-3p is significantly down-regulated in HCC. We identify a direct target of miR-199a-3p in HCC and reintroduction of miR-199a-3p to HCC cells strikingly suppressed cell migration and invasion in vitro in part by targeting CD151. In addition, a new bioanalytical method is validated to quantify miR-199a-3p levels in plasma and liver tissue for future Pharmacokinetic/Pharmacodynamic in vivo study. This bioanalytical method can be applied to other oligonucleotides therapeutic agents. ii miR-221 expression is upregulated in HCC patients. CD44 is responsible for cell- cell interaction, cell adhesion, cell migration and invasion and an important cancer stem cell marker. We report a direct correlation between miR-221 and CD44 expression in HCC cells; miR-221 and CD44 are low in epithelial-like HCC cells and high in mesenchymal- like HCC cells. Inhibition of miR-221 with antisense oligonucleotide negatively regulates CD44 expression at the translational level through the P13K-AKT-mTOR signaling pathway. The PI3K/AKT/mTOR signaling pathway is abnormally activated in HCC and sorafenib resistant cells. However, a recent phase III clinical trial with the allosteric mTOR inhibitor, everolimus failed to show better overall survival in patients with advanced HCC who were resistant or intolerant to sorafenib. Here we report that the ATP-competitive mTOR inhibitors showed better anti-proliferative and anti-migration effects on the mesenchymal-like HCC cells and sorafenib resistant HCC cells compared to everolimus. ATP-competitive mTOR inhibitors suppress CD44 expression by blocking phosphorylation of eukaryotic translation initiation factor eIF4E-binding protein 1, suggesting that ATP-competitive mTOR inhibitors would be more effective in treating the advanced HCC patients who are insensitive or resistant to sorafenib. Since miRNAs target entire pathways, miRNA-based therapy could be an effective option for treating HCC patients. miRNA-based therapy can be combined with small molecule ATP-competitive mTOR inhibitors such as INK128. We show here that these agents produce anti-proliferative and anti-migratory effects on mesenchymal-like HCC iii cells as well as sorafenib resistant HCC cells. Taken together, our findings aid in our understanding of the molecular mechanisms of sorafenib resistance in HCC and could contribute to the development of alternative strategies for treating advanced HCC who are intolerant or resistant to the current therapy. iv ACKNOWLEDGEMENTS First of all, I would like to thank my advisor, Dr. Schmittgen, for support and mentorship throughout my projects. He trained me to become an independent investigator and to improve my capabilities for better academic career. His enthusiasm for research extremely inspired me to pursue my goal with hard work and dedication. I also would like to thank my committee members, Dr. Jack Yalowich and Dr. Mitch Phelps for their critical advices on my research as well as warm encouragement. They always guided me to move my project in the right direction. Without all their support, I could not have finished my graduate study. I also would like to thank all my lab members for their help and friendship. At the beginning stage, Jong-Kook Park taught me the necessary techniques for research to set up the experiments. I would like to thank Dr. Jinmai Jiang, Ola Elgamel, Dhruvit Sutaria and Mohamed Badawi for their friendship and support. I would like to sincerely thank my parents, Ounsoo Kim and Samja Jang and my parents in law, Jongchul Lee and Jungja Choi for providing me all the support over the years and their continuous love. v Lastly, I would like to give special thanks to my family for their support and encouragement. I would like to thank my husband, Yun Soo Lee for his endless care and encouragement during the entire process and my son, Daniel Lee for his big smile. I could not have achieved it without them. Their love and support inspired me to continue to strive to become better. vi VITA 1997-2001………………………………… B.S., Pharmacy, Seoul National University, Seoul, South Korea 2001-2003………………………………… M.S., Pharmaceutics, Seoul National University, Seoul, South Korea 2008-2010, 2012-2015………………Graduate Teaching Associate/ Graduate Fellow, The Ohio State University, Columbus, Ohio, USA PUBLICATIONS 1. Jon C. Henry, Jong-Kook Park, Jinmai Jiang, Ji Hye Kim, Lewis R. Roberts, Soma Banerjee, Thomas D. Schmittgen. miR-199a-3p targets CD44 and reduces proliferation of CD44 positive hepatocellular carcinoma cell lines..Biochem Biophys Res Commun. 2010;403(1):120-5. 2. Jong-Kook Park, Takayuki Kogure, Gerard J. Nuovo, Jinmai Jiang, Lei He, Ji Hye Kim, Mitch A. Phelps, Tracey L. Papenfuss, Carlo M. Croce, Tushar Patel, and vii Schmittgen, T.D. miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res. 2011;71(24):7608-16. 3. Ji Hye Kim, Jong-Kook Park, Jinmai Jiang, Mohamed Badawi, Xiaokui Mo, Lewis R. Roberts and Thomas D. Schmittgen. Anti-invasion and anti-migration effects of miR-199a-3p in hepatocellular carcinoma are due in part to targeting CD151. Submitted 4. Ji Hye Kim, Mohamed Badawi, Jinmai Jiang and Thomas D. Schmittgen. ATP- competitive mTOR inhibitors exhibit anti-cancer effects in mesenchymal-like as well as sorafenib resistant hepatocellular carcinoma. Manuscript in preparation. viii Fields of Study Major Field – Pharmaceutics, Pharmacy ix Table of Contents Page Abstract…………………………………………………………………………………………………………………… ii Acknowledgements………………………………………………………………………………………………… v Vita ………………………………………………………………………………………………………………………… vii List of Tables……………………………………………………………………………………………………………xiii List of Figures………………………………………………………………………………………………………… xiv 1. Chapter 1: Introduction ............................................................................................ 1 1.1. Hepatocellular Carcinoma ................................................................................ 13 1.2. Non-coding RNAs .............................................................................................. 2 1.3. miRNAs in HCC ................................................................................................ 4 1.4. CD44 in cancers ................................................................................................. 7 1.5. Sorafenib and the acquired drug resistance in advanced HCC .......................... 8 1.6. PI3K-AKT-mTOR pathway in sorafenib resistant HCC .................................. 11 x 2. Chapter 2: Anti-invasion and anti-migration effects of miR-199a-3p in hepatocellular carcinoma are due in part to targeting CD151 ........................... 16 2.1. Introduction ...................................................................................................... 16 2.2. Methods ............................................................................................................ 18 2.3. Results .............................................................................................................. 22 2.4. Discussion ........................................................................................................ 25 3. Chapter 3: Development of a bioanalytical method for PK/PD of therapeutic miRNA mimics ........................................................................................................ 34 3.1. Introduction ...................................................................................................... 34 3.2. Materials and Methods ..................................................................................... 35 3.3. Results .............................................................................................................. 36 3.4. Discussion ........................................................................................................ 38 4. Chapter 4: Regulation of CD44 expression by miR-221 in hepatocellular carcinoma through PI3K-AKT-mTOR pathway ................................................. 43 4.1. Introduction ...................................................................................................... 43 4.2. Materials and Methods ..................................................................................... 45 4.3. Results .............................................................................................................
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