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Exploring the Role of Embryonic Liver Development Genes in HCV Induced Cirrhosis and Hepatocellular Carcinoma

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Exploring the Role of Embryonic Liver Development Genes in HCV Induced Cirrhosis and Hepatocellular Carcinoma Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2012 Growth gone awry: exploring the role of embryonic liver development genes in HCV induced cirrhosis and hepatocellular carcinoma Martha K. Behnke Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Life Sciences Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2928 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Martha Behnke 2012 All Rights Reserved i Growth gone awry: exploring the role of embryonic liver development genes in HCV induced cirrhosis and hepatocellular carcinoma Martha K. Behnke Dissertation submitted to the faculty of Virginia Commonwealth University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Integrative Life Sciences November 2012 Robert Fisher Carleton Garrett Mark Reimers, Chair Arun Sanyal Richard Sterling Timothy York ii Acknowledgements I would like to sincerely thank my supervisor Donna George for allowing me the opportunity to combine my doctoral studies with my work in the Hume-Lee Transplant Center, and my director Dr. Robert A. Fisher for graciously allowing me to work with the data from the A2ALL/GR2 study, as well as his unflagging enthusiasm and belief in me. I also appreciate the support encouragement that all of my colleagues in transplant have given me over the years! I would particularly like to thank my advisor, Mark Reimers, for taking me under his wing during a difficult period of starting over, and for allowing me the freedom to chase those interesting rabbits without letting me go too far down the rabbit hole! Finally, I need to thank my wonderful husband and best friend Bill, and my beautiful children Faith, Braedon, Nate, and Ryan. From special meals to taking the kids out on a Saturday so that I could study, and especially these last few months where you’ve all been “science orphans”, I could not have made this journey without your love, encouragement, and belief. Thank you. iii Table of Contents List of Tables ............................................................................................................................................... vii List of Figures ............................................................................................................................................. viii List of Abbreviations .................................................................................................................................... ix Chapter 1: Introduction and overview ......................................................................................................... 1 1.1 Motivation ..................................................................................................................................... 1 1.2 Hepatitis C infection, mechanisms of liver damage and hepatocarcinogenesis .......................... 3 1.3 Focus on liver development, healing, and regeneration .............................................................. 9 1.4 Developmental biology of the liver ............................................................................................. 10 1.4.1 Specification of hepatic fate ............................................................................................... 11 1.4.2 Formation of the hepatic bud ............................................................................................. 13 1.4.3 Liver bud growth ................................................................................................................. 15 1.4.4 Hepatocyte/ cholangiocyte cell fate determination ........................................................... 18 1.4.5 Hepatocyte maturation ....................................................................................................... 21 1.4.6 Post-natal development ...................................................................................................... 24 1.5 Molecular mechanisms in liver wound healing .......................................................................... 24 1.6 Molecular mechanisms in liver regeneration ............................................................................. 29 1.7 Conclusion ................................................................................................................................... 32 Chapter 2: Microarrays and processing methods ....................................................................................... 33 2.1 Introduction to microarray technology ............................................................................................ 33 2.2 Microarray data preparation and analysis .................................................................................. 35 iv 2.2.1 Quality Assessment metrics ................................................................................................ 36 2.2.2 Background correction and normalization ............................................................................... 39 2.3 Conclusion ................................................................................................................................... 44 Chapter 3. Analysis of developmental and regeneration gene expression in HCV-induced cirrhosis and HCC .............................................................................................................................................................. 45 3.1 Introduction ................................................................................................................................ 45 3.2 Patients and data collection methods ........................................................................................ 45 3.2.1 Sample preparation ............................................................................................................ 47 3.2.2 Data pre-processing methods ............................................................................................. 48 3.2.3 Description of patient population ....................................................................................... 49 3.2.4 Statistical methods .............................................................................................................. 50 3.2.5 Identification of test genesets ............................................................................................ 51 3.3 Results ......................................................................................................................................... 52 3.3.1 Expression of liver regeneration genes in cirrhosis and HCC .............................................. 52 3.3.2 Differential expression of liver healing genes ..................................................................... 54 3.3.3 Potential covariate effects on developmental gene expression in HCV-cirrhosis and HCC 56 3.3.4 Differential expression of liver development genes in HCV-cirrhosis and HCV-HCC .......... 59 3.4 Functional gene sets that discriminate between normal, cirrhosis, and tumor samples........... 64 3.4 Discussion .................................................................................................................................... 69 Chapter 4. CORRELATED EXPRESSION MODULES ...................................................................................... 75 4.1 Methods ...................................................................................................................................... 76 4.2 Correlated gene pattern results .................................................................................................. 77 4.2.1 Correlated genes in cirrhosis .............................................................................................. 77 4.2.2 Correlated genes in early HCC ............................................................................................ 79 4.3 Co-expression analysis ................................................................................................................ 80 4.3.1 Co-expression patterns in cirrhosis ..................................................................................... 81 4.3.2 Co-expression patterns in Early HCC ................................................................................... 82 Chapter 5. VALIDATION .............................................................................................................................. 87 5.1 Comparison with moderated t-test using limma ....................................................................... 87 5.1.1 Genome-wide testing results .............................................................................................. 88 5.1.2 Differentially expressed genes are specific to liver development ........................................... 89 5.2 Comparison with Gene Set Enrichment Analysis (GSEA) ............................................................ 93 v 5.2.1 Analysis of public gene sets and pathways ........................................................................ 94 5.2.2 GSEA of liver development genes ....................................................................................... 97 5.3 Validation to the Wurmbach dataset
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