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Roles of Adipose Tissue-Derived Factors in Adipose Tissue Development and Lipid Metabolism

Dissertation
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University

By
Jinsoo Ahn, M.S.
Graduate Program in Ohio State University Nutrition

The Ohio State University
2015

Dissertation Committee:
Kichoon Lee, Ph.D., Advisor
Earl H. Harrison, Ph.D. Ramesh Selvaraj, Ph.D.
Ouliana Ziouzenkova, Ph.D.
Copyright by Jinsoo Ahn
2015

Abstract

Obesity is a global trend and major risk factor for serious diseases including type 2 diabetes, heart disease, and hypertension. Obesity is characterized by excess fat accumulation, especially in the visceral area. The pathogenic effects related to common obesity are largely attributed to dysregulated secretion of adipokines followed by insulin resistance in peripheral tissues when adipose tissue mass is altered. White adipose tissue serves as a dynamic endocrine organ as well as a major energy reservoir for whole-body energy homeostasis. Adipokines influence various metabolic processes in the body including adipocyte differentiation; however, precise physiological roles of adipokines need to be further investigated. In addition, a large proportion of adipokines still needs to be identified.
Information from the gene expression omnibus (GEO) profile, a public repository for microarray data, combined with confirmatory studies on mRNA and protein expression were used to identify a novel adipose tissue-specific gene, chordin-like 1 (Chrdl1). Further analysis showed that Chrdl1 encodes a putative secreted protein which is a new adipokine. Chrdl1 expression increases during 3T3-L1 adipocyte development in vitro and mouse adipose tissue development in vivo. This pattern, combined with a dramatically increased lipid accumulation and adipocyte differentiation in Chrdl1- overexpressing 3T3-L1 cells suggests that Chrdl1 is a novel pro-adipogenic adipokine which plays stimulatory roles during adipocyte development.

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Adipose tissue is also of great significance in the production of food animals.
Reduction of adipose tissue mass will lead to partitioning dietary nutrients towards muscle instead of storage as fat, which enhances feed efficiency and decreases production costs. The net decrease in adiposity is achieved by down-regulation of fat accumulation and up-regulation of fat breakdown or lipolysis. The regulation of lipolysis is likely to be applied to control fat content and increase meat production. The initial step of lipolysis is catalyzed by adipose triglyceride lipase (ATGL) which is the rate-limiting step in this process. Comparative gene identification-58 (CGI-58) and G0/G1 switch gene 2 (G0S2) are known to be an activator and an inhibitor of ATGL-mediated lipolysis, respectively.
In the current study, porcine G0S2 was abundantly expressed in adipose tissue and the liver, and its expression was spatially confined in fat cell fraction and temporally specified in late developmental stages, suggesting that G0S2 expression is related to adipocyte development (pro-adipogenic) as well as inhibition of ATGL (anti-lipolytic). In another study, the expression of bovine G0S2 and CGI-58 in muscle of high-marbled steers of Hanwoo, a Korean cattle, was investigated. The regulation of lipolysis in muscle has a potential to increase marbling (intramuscular fat) in beef carcasses. The expression of G0S2 and CGI-58 was significantly higher in longissimus dorsi muscle of highmarbled steers than in less-marbled bulls, suggesting that both genes are novel candidate biomarkers of marbling in beef cattle. In addition, G0S2 was highly expressed in intramuscular fat portion separated from the longissimus dorsi muscle, whereas the expresson of CGI-58 was significantly higher in the remaining portion consisting of the longissimus dorsi muscle without intramuscular fat. It suggests that G0S2 inhibits ATGL- mediated lipolysis in intramuscular fat while CGI-58 activates ATGL in lipids of

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myocytes (intramyocellular triglycerides) which serves as an immediate source of energy during exercise.
In another recent study, RBP7 was identified as a novel adipose-specific gene in avian species through gene expression profiling after performing chicken microarray along with real-time PCR and Western blot analysis. Because the RBP7 promoter region was revealed to contain several potential binding sites for adipogenic transcription factors, transgenic quail containing a green fluorescent protein (GFP) gene under the control of the RBP7 promoter were generated by lentivirus-mediated gene transfer. GFP expression in transgenic quail was specific to adipose tissue and increased after adipocyte differentiation. These findings provide compelling evidence that the RBP7 promoter-gene construct can be used to overexpress target genes in adipose tissue.
In conclusion, this study has found a new visceral adipokine (Chrdl1), marbling biomarkers (G0S2 and CGI-58), and an adipose-specific gene (RBP7) and its promoter for overexpression of target genes in vivo. It has been shown that Chrdl1 increases lipid accumulation and adipocyte differentiation of 3T3L1 preadipocytes. Expressions of G0S2 and CGI-58, regulators of ATGL-mediated lipolysis, were significantly higher in longissimus dorsi muscle of high-marbled steers. Avian RBP7 gene showed an exclusive expression adipose tissue, and its promoter was used to generate transgenic quail expressing a target gene (GFP) in adipose tissue. Together, this study advances adipose tissue biology through identification of genes related to adipokine, marbling, and adipose-specific expression.

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Acknowledgements

First, I would like to express my sincere gratitude to my advisor, Dr. Kichoon Lee, for offering me the opportunity to conduct this research. His continuous guidance and support helped me the entire time required to accomplish my doctoral research. I am grateful of sharing his experience, knowledge, and enthusiasm. Without his advice, this study would not have been successful.
I also would like to sincerely thank members of my dissertation committee, Dr.
Earl Harrison, Dr. Ramesh Selvaraj and Dr. Ouliana Ziouzenkova for their insightful comments and all the encouragements.
I would like to appreciate to Dr. Jeff Firkins, the director of my Interdisciplinary
Ph.D. Program in Nutrition, and Ms. Amanda Hargett, the program manager, for their instructions and advice from start to finish.
I would also thank all of previous and current members in the Lee Lab and my colleagues and fellow students: Ms. Yeunsu Suh, Dr. Sangsu Shin, Aishlin Lee, Xiang Li, Dr. Yan Song, Shujin Yang, Dr. Young Min Choi, Jibin Zhang, Paula Chen, Elizabeth Kim, Ju Yeon Park for their suggestions and kind assistance, and Dr. Henry Zerby, Dr. Steven Moeller, Dr. Macdonald Wick, Dr. Joe Ottobre, Ann Ottobre, Ben Wenner, Mike Cressman, Yang Cheng, and all other colleagues in the Dept. Animal Sciences for their support and collaborations.

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Finally, I would like to give my gratefulness to my late father (Prof. Jong-Cheol
Ahn), mother (Seung-Hae Jung), and brother (Taesoo Ahn) for encouraging me to pursue this degree and supporting me throughout my life.

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Vita

1999 ...............................................................B.S. Biotechnology, Yonsei University,
Seoul, Korea
2011 ...............................................................M.S. Foods and Nutrition, Ohio University 2011 to present ..............................................Graduate Research Associate,
Ohio State University Nutrition, The Ohio State University

Publications

1. Ahn J, Oh SA, Suh Y, Moeller SL, Lee K. (2013) Porcine G0/G1 switch gene 2 (G0S2) expression is regulated during adipogenesis and short-term in-vivo nutritional interventions. Lipids, 48(3):209–18.

2. [Song Y, Ahn J], Suh Y, Davis ME, Lee K. (2013) Identification of novel tissuespecific genes by analysis of microarray databases: a human and mouse model. PLoS One, 8(5):e64483.

3. Ahn J, Li X, Choi YM, Shin S, Oh SA, Suh Y, Nguyen TH, Baik M, Hwang S, Lee K.
(2014) Differential expressions of G0/G1 switch gene 2 and comparative gene identification 58 are associated with fat content in bovine muscle. Lipids, 49(1):1–14.

4. [Hassan A, Ahn J], Suh Y, Choi YM, Chen P, Lee K. (2014) Selenium promotes adipogenic determination and differentiation of chicken embryonic fibroblasts with regulation of genes in fatty acid uptake, triacylglycerol synthesis, and lipolysis.

Journal of Nutritional Biochemistry, 25(8):858–67.

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5. Zhang J, Suh Y, Choi YM, Ahn J, Davis ME, Lee K. (2014) Differential expression of cyclin G2, cyclin dependent kinase inhibitor 2C and peripheral myelin protein 22 genes during adipogenesis. Animal, 8(5):800–9.

6. Choi YM, Suh Y, Ahn J, Lee K. (2014) Muscle hypertrophy in heavy weight
Japanese quail line: Delayed muscle maturation and continued muscle growth with prolonged upregulation of myogenic regulatory factors. Poult Sci, 93(9):2271–7.

7. Ahn J, Shin S, Suh Y, Park JY, Hwang S, Lee K. (2015) Identification of the avian
RBP7 gene as a new adipose-specific gene and RBP7 promoter-driven GFP expression in adipose tissue of transgenic quail. PLoS One, 10(4):e0124768.

Fields of study

Major Field: Ohio State University Nutrition

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Table of Contents

Abstract............................................................................................................................... ii Acknowledgments............................................................................................................... v Vita.................................................................................................................................... vii Table of Contents............................................................................................................... ix List of Tables ...................................................................................................................xiii List of Figures.................................................................................................................. xiv List of Abbreviations ....................................................................................................... xvi Chapter 1: Introduction...................................................................................................... 1 Chapter 2: Review of the literature..................................................................................... 4
2.1. Physiology and pathophysiology of adipose tissue.................................................. 4 2.2. Adipokines and endocrine functions of white adipose tissue .................................. 7 2.3. Development of adipocytes...................................................................................... 9
2.3.1. Cell origin of adipocytes ................................................................................... 9 2.3.2. Commitment...................................................................................................... 9
2.3.2.1. Mesenchymal stem cells (MSCs).............................................................. 10 2.3.2.2. Factors involved in the commitment step ................................................. 10 2.3.2.3. Bone Morphogenetic Protein (BMP) and commitment ............................ 11

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2.3.2.4. Wnt signaling and commitment ................................................................ 12 2.3.2.5. Hedgehog signaling and commitment....................................................... 15 2.3.2.6. Zfp423 and commitment........................................................................... 16
2.3.3. Terminal differentiation .................................................................................. 17
2.3.3.1. Preadipocyte cell line ................................................................................ 17 2.3.3.2. Growth arrest and induction of differentiation.......................................... 18 2.3.3.2. The roles of C/EBPβ and mitotic clonal expansion .................................. 18 2.3.3.4. Early stage of transcriptional network ...................................................... 20 2.3.3.5. Late stage of transcriptional network........................................................ 21 2.3.3.6. Bone Morphogenetic Protein (BMP) and the differentiation.................... 22 2.3.3.7. Wnt signaling and the differentiation........................................................ 23
2.4. The role of chordin-like 1 as a BMP regulator during adipogenesis ..................... 24
2.4.1. Chordin............................................................................................................ 24 2.4.2. Potential roles of Chordin-like 1 during adipogenesis.................................... 24
2.5. Discovery of adipose-specific genes by cDNA microarray-based gene expression

Profiling……………………………………………………………………..…….26

Chapter 3: Expression of a novel adipose tissue-specific Chordin-like 1 gene and its influence on adipocyte development ................................................................................ 29
3.1. Abstract .................................................................................................................. 29 3.2. Introduction............................................................................................................ 31 3.3. Materials and Methods........................................................................................... 32 3.4. Results.................................................................................................................... 37 3.5. Discussion .............................................................................................................. 41

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3.6. Acknowledgements................................................................................................ 45
Chapter 4: Porcine G0/G1 Switch Gene 2 (G0S2) expression is regulated during adipogenesis and short-term in vivo nutritional interventions .......................................... 51
4.1. Abstract .................................................................................................................. 51 4.2. Introduction............................................................................................................ 53 4.3. Materials and Methods........................................................................................... 55 4.4. Results.................................................................................................................... 60 4.5. Discussion .............................................................................................................. 65 4.6. Acknowledgements................................................................................................ 70
Chapter 5: Differential expressions of G0/G1 switch gene 2 and comparative gene identification-58 are Aassociated with fat content in bovine muscle……………………79
5.1. Abstract .................................................................................................................. 79 5.2. Introduction............................................................................................................ 81 5.3. Materials and Methods........................................................................................... 82 5.4. Results.................................................................................................................... 88 5.5. Discussion .............................................................................................................. 92 5.6. Acknowledgements................................................................................................ 98
Chapter 6: Identification of the avian RBP7 gene as a new adipose-specific gene and RBP7 promoter-driven GFP expression in adipose tissue of transgenic quail…………109
6.1. Abstract ................................................................................................................ 109 6.2. Introduction.......................................................................................................... 111 6.3. Materials and Methods......................................................................................... 112 6.4. Results.................................................................................................................. 120

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6.5. Discussion ............................................................................................................ 123 6.6. Acknowledgements.............................................................................................. 127

Chapter 7: Summary………….……………………………….…………..……………136

Chapter 8: Concluding remarks……………………………….…………..……………139 References....................................................................................................................... 141

xii

List of Tables

Table 6.1. Production of transgenic quail using lentivirus-mediated gene transfer into

stage X quail embryos…………………………………………………………………135

xiii

List of Figures

Figure 2.1. Adipokines grouped according to their physiologic roles…..……….…….....9

Figure 2.2. BMP/smad signaling during the adipogenic commitment..………………....12 Figure 2.3. Wnt signaling during the adipogenic commitment and differentiation.....…..15 Figure 2.4. Hedgehog signaling during the adipogenic commitment..…………………..16

Figure 2.5. Zfp423-mediated up-regulation of adipogenesis…….…….…………….…..17

Figure 2.6. Adipocyte terminal differentiation and regulating factors…………………..22

Figure 2.7. Proposed inhibitory function of Chrdl1 against BMP signaling…….………26 Figure 3.1. Relative Chrdl1 mRNA expression in various tissues …...……..…………..46 Figure 3.2. Chrdl1 mRNA and protein expression ……………………………………...47 Figure 3.3. Developmental regulation of Chrdl1 expression ……………………………48

Figure 3.4. Increased adipocyte differentiation by Chrdl1 overexpression….…………..49

Figure 3.5. Alternative splicing of Chrdl1………………………………………………50 Figure 4.1. Comparison of G0S2 amino acid sequences………….……………………..71 Figure 4.2. Tissue distribution of porcine G0S2…………………………………..……..72 Figure 4.3. Porcine G0S2 gene expression in SV and fat cell fraction…...……………..73 Figure 4.4. Porcine G0S2 gene expression during adipocyte differentiation…….….…..74

Figure 4.5. Porcine G0S2 gene expression during adipose tissue development……..…..75 Figure 4.6. Porcine G0S2 gene expression during nutritional intervention.……………..76

Figure 4.7. Alignment of G0S2 nucleotide sequences.………………………..…………77

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Figure 5.1.Alignment of G0S2 coding sequences………………....………………...…..99

Figure 5.2. Alignment of CGI-58 coding sequences ……………………..…………....100

Figure 5.3. Homology analysis of G0S2 amino acid sequences…………….…….……102

Figure 5.4. Homology analysis of CGI-58 amino acid sequences ....………………......103 Figure 5.5. Alternative splicing patterns of bovine CGI-58..……………..…………....105 Figure 5.6. Tissue distribution of bovine G0S2 and CGI-58 mRNA……….…….……106 Figure 5.7. The mRNA expressions of FABP4, G0S2 and CGI-58 in Hanwoo ….……107

Figure 6.1. RBP7 mRNA expression in various tissues…………………….…….……128 Figure 6.2. RBP7 amino acid sequences and protein expression ….……….…….……129 Figure 6.3. Analysis of RBP7 promoter ………………………..….……….…….….…130

Figure 6.4. GFP expression in various tissues of selected lines under UV light.....……131 Figure 6.5. GFP expression in SV and fat cell fractions and during primary adipocyte

differentiation …………………………………………..………….……….……..……132 Figure 6.6. Alignment of RBP7 nucleotide sequences.………………….……………..133 Figure 6.7. GFP expression in various tissues under UV light.....…..…………………134

xv

List of Abbreviations

ATGL…………………………………………..…...Adipose triglyceride lipase

BMP……………………………………….………Bone morphogenetic protein

C/EBP ……………………………………………..CCAAT/enhancer-binding protein CGI-58 ........................................................……Comparative gene identification-58

Chrdl1……………………………………………Chordin-like 1

FC................................................................……Fat cell

G0………………………………………………Generation 0 G1………………………………………………Generation 1 G2………………………………………………Generation 2

GEO………………………………………..Gene expression omnibus G0S2 ............................................................ G0/G1 Switch Gene 2 IMF ………………………………………..Intramuscular fat IMTG…………………………………….Intramyocellular triglycerides

MSC………………………………….…Mesenchymal stem cell

PPAR ………………………………..Peroxisome proliferator-activated receptor gamma qPCR.………………………………….Quantitative real-time PCR RBP7 ………………………………….Retinol .binding protein 7 TAG.…………………………………..Triacylglycerol SV……………………………………….Stromal-vascular

xvi

Chapter 1: Introduction

The rapid increase in obesity over the past few decades has become a public health problem in most developed countries (Bleich et al., 2008). More than 1.4 billion adults worldwide were overweight, and at least 500 million of them were obese in 2008 (World Health Organization, 2013). In the United States, nearly two-thirds of the adult population is overweight and approximately one-third is obese (Centers for Disease Control and Prevention, 2013). It has been shown that obesity is highly associated with the incidence of a number of diseases, including type 2 diabetes, hypertension, dyslipidemia, and metabolic syndrome (Nguyen et al., 2008). Obesity is characterized by excess accumulation of adipose tissue, particularly in the visceral compartment, and dysregulated secretion of adipokines which leads to decreased insulin sensitivity in peripheral tissues, including skeletal muscle and the liver (Galic et al., 2010). Adipose tissue is a metabolically dynamic endocrine organ that plays a critical role in the maintenance of whole-body energy homeostasis. White adipose tissue, the predominant type of adipose tissue, was identified as a major site for secretion of bioactive peptides, collectively named adipokines, as well as storage of excess energy as triglycerides (Kershaw & Flier, 2004).
Adipokines influence various metabolic processes, such as fatty acid metabolism, insulin sensitivity, adipocyte differentiation, angiogenesis, and inflammation (Dyck et al., 2006). Among adipokines that have been identified, some of them, such as leptin, are

1

well-characterized, but their precise physiological roles need to be further investigated. As noted previously, approximately 40% of expressed genes in adipose tissue that are currently unknown, and about 20% of these unknown genes may encode secretory proteins (Maeda et al., 1997; Kershaw & Flier, 2004). The identification of unknown genes that encode adipose-specific secretory proteins along with the continued characterization of known genes is likely to provide further insight into the endocrine function of adipose tissue. The pathogenic effects associated with obesity are possibly due to modifications in secretion of unknown adipokines when adipose tissue mass is altered.
In addition, adipose tissue is of great importance in the food animal industry, as decreasing adiposity is a main determinant for feed efficiency of partitioning nutrients from feed into food products, such as muscle. Considering feed as a major component of production costs, increasing feed efficiency by reducing adipose tissue mass has great economic value in the meat-producing enterprise. The net reduction of adipose tissue mass can be achieved by decreasing fat deposition and increasing the breakdown of fat (lipolysis) in adipose tissue, which ultimately leads to repartitioning of energy from adipose tissue to other peripheral tissues and transferring nutrients from feed to muscle. Genomic selection for improving feed efficiency is an important breeding objective (Pryce et al., 2014). Beef cattle and pork production are significant components of agriculture and diets throughout the world. As global demand increases, in 2015, international beef and pork exports are forecasted to grow by nearly 2 percent to a record 9.9 million tons and 4 percent to 7.2 million tons, respectively (USDA, FAS., 2014). To meet the growing demand, beef and pork producers will need to increase meat production

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    Trim24-Regulated Estrogen Response Is Dependent on Specific Histone Modifications in Breast Cancer Cells

    The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2012 TRIM24-REGULATED ESTROGEN RESPONSE IS DEPENDENT ON SPECIFIC HISTONE MODIFICATIONS IN BREAST CANCER CELLS Teresa T. Yiu Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Biochemistry Commons, Cancer Biology Commons, Medicine and Health Sciences Commons, and the Molecular Biology Commons Recommended Citation Yiu, Teresa T., "TRIM24-REGULATED ESTROGEN RESPONSE IS DEPENDENT ON SPECIFIC HISTONE MODIFICATIONS IN BREAST CANCER CELLS" (2012). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 313. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/313 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. TRIM24-REGULATED ESTROGEN RESPONSE IS DEPENDENT ON SPECIFIC HISTONE
  • Downloaded from Bioscientifica.Com at 10/03/2021 12:22:59PM Via Free Access

    Downloaded from Bioscientifica.Com at 10/03/2021 12:22:59PM Via Free Access

    61 1 Journal of Molecular S Iyer and S K Agarwal Epigenetic regulation in 61:1 R13–R24 Endocrinology endocrine cells REVIEW Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types Sucharitha Iyer and Sunita K Agarwal Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA Correspondence should be addressed to S K Agarwal: [email protected] Abstract Epigenetic regulation is emerging as a key feature in the molecular characteristics of Key Words various human diseases. Epigenetic aberrations can occur from mutations in genes f neuroendocrine associated with epigenetic regulation, improper deposition, removal or reading of f pancreas histone modifications, DNA methylation/demethylation and impaired non-coding f parathyroid RNA interactions in chromatin. Menin, the protein product of the gene causative for f pituitary the multiple endocrine neoplasia type 1 (MEN1) syndrome, interacts with chromatin- associated protein complexes and also regulates some non-coding RNAs, thus participating in epigenetic control mechanisms. Germline inactivating mutations in the MEN1 gene that encodes menin predispose patients to develop endocrine tumors of the parathyroids, anterior pituitary and the duodenopancreatic neuroendocrine tissues. Therefore, functional loss of menin in the various MEN1-associated endocrine cell types can result in epigenetic changes that promote tumorigenesis. Because epigenetic changes are reversible, they can be targeted to develop therapeutics for restoring the tumor epigenome to the normal state. Irrespective of whether epigenetic alterations are the cause or consequence of the tumorigenesis process, targeting the endocrine tumor- associated epigenome offers opportunities for exploring therapeutic options. This review presents epigenetic control mechanisms relevant to the interactions and targets of menin, and the contribution of epigenetics in the tumorigenesis of endocrine cell types Journal of Molecular from menin loss.
  • Differential Expression Profile Prioritization of Positional Candidate Glaucoma Genes the GLC1C Locus

    Differential Expression Profile Prioritization of Positional Candidate Glaucoma Genes the GLC1C Locus

    LABORATORY SCIENCES Differential Expression Profile Prioritization of Positional Candidate Glaucoma Genes The GLC1C Locus Frank W. Rozsa, PhD; Kathleen M. Scott, BS; Hemant Pawar, PhD; John R. Samples, MD; Mary K. Wirtz, PhD; Julia E. Richards, PhD Objectives: To develop and apply a model for priori- est because of moderate expression and changes in tization of candidate glaucoma genes. expression. Transcription factor ZBTB38 emerges as an interesting candidate gene because of the overall expres- Methods: This Affymetrix GeneChip (Affymetrix, Santa sion level, differential expression, and function. Clara, Calif) study of gene expression in primary cul- ture human trabecular meshwork cells uses a positional Conclusions: Only1geneintheGLC1C interval fits our differential expression profile model for prioritization of model for differential expression under multiple glau- candidate genes within the GLC1C genetic inclusion in- coma risk conditions. The use of multiple prioritization terval. models resulted in filtering 7 candidate genes of higher interest out of the 41 known genes in the region. Results: Sixteen genes were expressed under all condi- tions within the GLC1C interval. TMEM22 was the only Clinical Relevance: This study identified a small sub- gene within the interval with differential expression in set of genes that are most likely to harbor mutations that the same direction under both conditions tested. Two cause glaucoma linked to GLC1C. genes, ATP1B3 and COPB2, are of interest in the con- text of a protein-misfolding model for candidate selec- tion. SLC25A36, PCCB, and FNDC6 are of lesser inter- Arch Ophthalmol. 2007;125:117-127 IGH PREVALENCE AND PO- identification of additional GLC1C fami- tential for severe out- lies7,18-20 who provide optimal samples for come combine to make screening candidate genes for muta- adult-onset primary tions.7,18,20 The existence of 2 distinct open-angle glaucoma GLC1C haplotypes suggests that muta- (POAG) a significant public health prob- tions will not be limited to rare descen- H1 lem.
  • Insulin-Like Growth Factor Receptor Signaling in Tumorigenesis and Drug

    Insulin-Like Growth Factor Receptor Signaling in Tumorigenesis and Drug

    Hua et al. Journal of Hematology & Oncology (2020) 13:64 https://doi.org/10.1186/s13045-020-00904-3 REVIEW Open Access Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy Hui Hua1, Qingbin Kong2, Jie Yin2, Jin Zhang2 and Yangfu Jiang2* Abstract Insulin-like growth factors (IGFs) play important roles in mammalian growth, development, aging, and diseases. Aberrant IGFs signaling may lead to malignant transformation and tumor progression, thus providing the rationale for targeting IGF axis in cancer. However, clinical trials of the type I IGF receptor (IGF-IR)-targeted agents have been largely disappointing. Accumulating evidence demonstrates that the IGF axis not only promotes tumorigenesis, but also confers resistance to standard treatments. Furthermore, there are diverse pathways leading to the resistance to IGF-IR-targeted therapy. Recent studies characterizing the complex IGFs signaling in cancer have raised hope to refine the strategies for targeting the IGF axis. This review highlights the biological activities of IGF-IR signaling in cancer and the contribution of IGF-IR to cytotoxic, endocrine, and molecular targeted therapies resistance. Moreover, we update the diverse mechanisms underlying resistance to IGF-IR-targeted agents and discuss the strategies for future development of the IGF axis-targeted agents. Keywords: Insulin-like growth factor, Cancer, Receptor tyrosine kinase, Tumorigenesis, Drug resistance Introduction macrophages (Fig. 1). Furthermore, the bioavailability of Sustained growth is a typical hallmark of cancer. Growth IGF is regulated by IGF-binding proteins (IGFBPs), factors, such as epidermal growth factor (EGF), trans- which are identified as the serum reservoirs of IGF [1].
  • Robles JTO Supplemental Digital Content 1

    Robles JTO Supplemental Digital Content 1

    Supplementary Materials An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma based on mRNA, microRNA and DNA Methylation Biomarkers Ana I. Robles1, Eri Arai2, Ewy A. Mathé1, Hirokazu Okayama1, Aaron Schetter1, Derek Brown1, David Petersen3, Elise D. Bowman1, Rintaro Noro1, Judith A. Welsh1, Daniel C. Edelman3, Holly S. Stevenson3, Yonghong Wang3, Naoto Tsuchiya4, Takashi Kohno4, Vidar Skaug5, Steen Mollerup5, Aage Haugen5, Paul S. Meltzer3, Jun Yokota6, Yae Kanai2 and Curtis C. Harris1 Affiliations: 1Laboratory of Human Carcinogenesis, NCI-CCR, National Institutes of Health, Bethesda, MD 20892, USA. 2Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan. 3Genetics Branch, NCI-CCR, National Institutes of Health, Bethesda, MD 20892, USA. 4Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan. 5Department of Chemical and Biological Working Environment, National Institute of Occupational Health, NO-0033 Oslo, Norway. 6Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), 08916 Badalona (Barcelona), Spain. List of Supplementary Materials Supplementary Materials and Methods Fig. S1. Hierarchical clustering of based on CpG sites differentially-methylated in Stage I ADC compared to non-tumor adjacent tissues. Fig. S2. Confirmatory pyrosequencing analysis of DNA methylation at the HOXA9 locus in Stage I ADC from a subset of the NCI microarray cohort. 1 Fig. S3. Methylation Beta-values for HOXA9 probe cg26521404 in Stage I ADC samples from Japan. Fig. S4. Kaplan-Meier analysis of HOXA9 promoter methylation in a published cohort of Stage I lung ADC (J Clin Oncol 2013;31(32):4140-7). Fig. S5. Kaplan-Meier analysis of a combined prognostic biomarker in Stage I lung ADC.
  • Supplementary Table 1: Selected Gene Products Used in Cdna Based Array 31

    Supplementary Table 1: Selected Gene Products Used in Cdna Based Array 31

    Supplementary Table 1: Selected gene products used in cDNA based array 31. Betacellulin BC011618 analysis 32. 3beta hydroxysteroid dehydrogenase M27137 33. 17beta hydroxy steroid degydrogenase BC020710 Serial Gene name (GenBank accession #) 34. Bone morphogenetic protein 1 M22488 35. Bone morphogenetic protein 2 M22489 1. Actin beta X00351 36. Bone morphogenetic protein 3 M22491 2. Actinin alpha 1 X15804 37. Bone morphogenetic protein 4 D30751 3. Actinin alpha 2 M86406 38. Bone morphogenetic protein 5 M60314 4. Actinin alpha 3 M86407 39. Bone morphogenetic protein 6 M60315 5. Activin A receptor type II-like 1 L17075 40. Bone morphogenetic protein 7 M60316 6. Activin A receptor type IB U14722 41. Bone morphogenetic protein 8 M97016 7. Actvin A receptor type II X77533 42. Bradykinin NM_000623 8. Alpha 1anti-trypsin K01396 43. Bradykinin beta2 receptor M88714 9. Alpha fetoproteinV V51514 44. Bystin L36720 10. Alphav beta3 integrin NM_002210 45. C3 complement AY513239 11. Alpha macroglobulin 1 M163959 46. Cdx 2 U51096 12. Alpha macroglobulin 2 M11313 47. C-fos U62538 13. 5alpha reductase NM_000348 48. C-jun NM_002228 14. 17 alpha hydroxylase AH002665 49. C-myc V00568 15. Aminopeptidase A L12468 50. CA 125 EF026424 16. Aminopeptidase N NM_001935 51. Cadherin P X63629 17. Amphiregulin L41352 52. Calcitonin alpha J00109 18. Androgen receptor M20132 53. Calcitonin beta BC093468 19. Angiopoietin 1 U83508 54. Calcitonin receptor L00587 20. Angiotensin receptor 1 M87290 55. Cardiotrophin 1 U43030 21. Angiopoietin 2 NM_001147 56. Cathepsin B M14221 22. Apolipoprotein E M12529 57. Cathepsin D M11233 23. Apolipoprotein J NM_001831 58. Cathepsin L X12451 24. Arachidonate 5-lipooxygenase J03571 59.