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Abstract Hepatocyte Specific Gp73/Golm1 Knockout Mice

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Abstract Hepatocyte Specific Gp73/Golm1 Knockout Mice ABSTRACT HEPATOCYTE SPECIFIC GP73/GOLM1 KNOCKOUT MICE AND HUMAN HEPATOCELLULAR CARCINOMA CELL LINES PROVIDE INSIGHTS INTO THE POTENTIAL ROLES OF GP73 HCC SERUM BIOMARKER Gunisha Arora, Ph.D. Department of Biological Sciences Northern Illinois University, 2016 Barrie P. Bode, Director Golgi Protein – 73kDa (GP73/GOLM1) is a resident cis-Golgi Type II membrane protein that is nearly undetectable in normal hepatocytes, but its expression increases in hepatocytes during hepatocellular carcinoma (HCC) and its serum levels increase in patients with chronic hepatitis C infection and HCC, yet its biological role in the liver and in the pathogenesis of HCC remains unclear. In order to investigate possible biological roles for GP73, hepatocyte-specific GOLM1 null mice (C57BL/6) were created using the Cre-loxP system, with “floxed” GOLM1 gene exon 3 and Cre recombinase driven by the albumin promoter. Mouse genotypes were confirmed by PCR analysis. GOLM1Fl/Fl/Cre(+) animals showed no obvious biological phenotype compared to their Cre(-) littermates. They exhibited normal growth, behaviors, and mated successfully, suggesting that hepatic GP73 is not vital for normal physiological function. Consistent with clinical observations in humans, GP73 expression increased in a chemically induced model of mouse liver fibrosis and carcinogenesis. Examination of GP73 expression in 14 human HCC cell lines revealed that GP73 is consistently expressed in mesenchymal HCC cells (modeling metastatic) but not in most epithelial HCC cell lines. Cell invasion assays indicated that mesenchymal HCC with high GP73 expression were more invasive suggesting a potential role for this protein in metastasis. Silencing in invasive mesenchymal HCC cells suggested that GP73 is necessary for enhanced cell proliferation and over-expression in a non-invasive epithelial HCC cell line suggested that GP73 is sufficient to induce epithelial to mesenchymal transition (EMT) and metastasis. Collectively the results suggest GP73 will serve as a potential therapeutic target for treatment of advanced HCC and that the hepatocyte-specific GP73 knockout mice will serve as a valuable tool to investigate the role of GP73 in HCC development. NORTHERN ILLINOIS UNIVERSITY DE KALB, ILLINOIS AUGUST 2016 HEPATOCYTE SPECIFIC GP73/GOLM1 KNOCKOUT MICE AND HUMAN HEPATOCELLULAR CARCINOMA CELL LINES PROVIDE INSIGHTS INTO THE POTENTIAL ROLES OF GP73 HCC SERUM BIOMARKER BY GUNISHA ARORA ©2016 Gunisha Arora A DISSERTATION SUBMITTED TO THE GRADUATE SCHOOL IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE DOCTOR OF PHILOSOPHY DEPARTMENT OF BIOLOGICAL SCIENCES Doctoral Director: Barrie P. Bode ACKNOWLEDGEMENTS I would like to thank my mentor, Dr. Barrie P. Bode, for always being there to support me. His interest in this field is aspiring and his kindness is unmatched. I would like to thank Dr. Claus Fimmel for discovering GP73 in 2000, thereby providing me with such an interesting project. I am thankful to Dr. Corinna Kashuba for her advice and guidance, and for training me in the proper handling of animals. I thank Dr. Sherine Elsawa and Dr. Linda Yasui for their feedback and for being such an integral part of my committee and the cancer journal club. Also, I would like to thank Dr. Thomas Sims and Dr. Ken Gasser for being such great advisors. Additionally, I am thankful to Dr. Bryan Fuchs, Dr. Lorinda Wright and Dr. Gulam Warris for collaborating with us on several projects. A special thanks to Rosalba, Jessica, John and Natalie for being the best under-graduates I have had the pleasure to teach, learn from and work with on this project. I am grateful to Northern Illinois University for giving me this opportunity to work with a community of helpful people and for giving me a Teaching Assistantship. Staying away from home, my friends have been my pillars supporting me in every step I take, so I thank AJ, Aashi, Pooja, Arnab, Aparna, Shishir, John, Clare, Evan, Daksha, Prasanth, and Poornima for being my pillars. I can't thank enough my lab mothers, Clare and Paige for sharing with me their protocols and the know-how of lab-work. Also, I am truly thankful to the members of the Network of Nations, Ruth, Dan, Glenn and Shirley who have supported international students like me in several ways. Finally, I wish to thank my dear family; Jagjit Singh Arora and Rashema Arora, my parents; Dr. Sumeet Arora, Dr. Gaurav Arora and Jasmine, my sister, brother-in-law and their daughter; and Harsheil Arora, my brother; for the immense love and support, and for making me a better person. TABLE OF CONTENTS Page LIST OF TABLES.................................................................................................... vi LIST OF FIGURES.................................................................................................. vii INTRODUCTION.................................................................................................... 1 HCC................................................................................. 1 GOLM1/GP73/GOLPH2................................................. 2 MATERIAL AND METHODS............................................................................... 6 In vitro studies................................................................. 6 HCC Cell lines and cell culture........................... 6 GP73 shRNA silencing....................................... 8 Forced Over-expression of GP73........................ 14 Western Blot analysis.......................................... 15 Validation of GP73 anti-sera............................... 17 Generation of growth curves............................... 18 Growth Inhibition assays..................................... 19 Transport assays................................................... 20 Invasion assay...................................................... 22 RNA Analysis...................................................... 23 In vivo studies................................................................... 26 Generation of liver-specific GP73 knockout mice. 26 Tissue isolation and blood collection .................... 31 Tissue processing for RNA and proteins................ 32 iv Page GP73 AND SUSTAINED CELL PROLIFERATION............................................. 33 Introduction...................................................................... 33 Scientific Aims................................................................. 38 Results.............................................................................. 38 Conclusions...................................................................... 55 GP73, METASTASIS AND INVASION................................................................. 57 Introduction...................................................................... 57 Scientific Aims................................................................. 58 Results.............................................................................. 59 Conclusions...................................................................... 64 GP73 AND LIVER INFLAMMATION................................................................... 71 Introduction...................................................................... 71 Scientific Aims................................................................ 72 Results............................................................................. 73 Conclusions..................................................................... 78 LIVER-SPECIFIC GP73 KNOCKOUT MICE...................................................... 79 Introduction..................................................................... 79 Scientific Aims............................................................... 80 Results............................................................................. 81 Conclusions..................................................................... 85 v Page SUMMARY, DISCUSSION AND FUTURE DIRECTIONS................................. 86 REFERENCES......................................................................................................... 93 LIST OF TABLES Table Page 1. GIPZ lentiviral shRNA Sense and Antisense sequences and their targets............. 11 2. List of cell lines electroporated with GIPZ GOLM1 shRNA plasmids.................. 13 3. Cell densities plated for specific cell lines.............................................................. 19 4. PCR programs for the three different primer pairs.................................................. 30 5. Number of experimental (LSKO) and control mice obtained from 57 breeding experiments.............................................................................................................. 81 6. Summary of GP73 transfected cell lines and their cell proliferation, glutamine and leucine uptake, and ASCT2 and LAT1 expression............................................ 86 7. Summary of expression of GP73, E-cadherin and vimentin in the 13 different HCC cell lines along with their invasion assay results............................................ 87 8. Summary of GP73 transfected cell lines and their invasion assay results along with E-cadherin and Vimentin expression................................................................. 88 LIST OF FIGURES Figure Page 1. Upregulated cleavage and secretion of GP73.......................................................... 3 2. Model of GP73 dimer.............................................................................................. 4 3. Progressive
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