Expression Profile Analysis Identifies Key
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SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy
SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Zhang, Huadi. 2017. SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:42061511 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy A dissertation presented by Huadi Zhang to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Biological and Biomedical Sciences Harvard University Cambridge, Massachusetts August 2017 © 2017 Huadi Zhang All rights reserved. Dissertation Advisor: Professor David Pellman Huadi Zhang SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy Abstract Oncogenic transformation is often accompanied by chromosome instability, an increased rate of chromosome missegregation. The consequent gain or loss of chromosomes—termed aneuploidy—hinders the growth of most non-cancerous tissues, but is prevalent in tumors. During tumorigenesis, aneuploidy contributes to cellular heterogeneity and may promote downstream mutations, including chromosome rearrangements and oncogene amplification. Cellular mechanisms that safeguard against aneuploidy remain unclear. The Hippo pathway is a tumor-suppressor mechanism with essential roles in regulating tissue homeostasis. -
Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in -
An Epigenetic Genome-Wide Screen Identifies SPINT2 As a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma
Research Article An Epigenetic Genome-Wide Screen Identifies SPINT2 as a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma Paul N. Kongkham,1 Paul A. Northcott,2 Young Shin Ra,1 Yukiko Nakahara,2 Todd G. Mainprize,1 SidneyE. Croul, 3 Christian A. Smith,1 Michael D. Taylor,2 and James T. Rutka1 1Program in Cell Biology and 2Program in Developmental and Stem Cell Biology, Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, and 3Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada Abstract transmembrane receptor Patched (PTCH) or the Wnt signaling member APC, respectively (8, 9). PTCH mutations are found in Medulloblastoma (MB) is a malignant cerebellar tumor that f occurs primarily in children. The hepatocyte growth factor 10% of sporadic MB cases (10). Other Hedgehog pathway members (HSUFU, SMO, and PTCH2) are implicated in fewer cases (HGF)/MET pathway has an established role in both normal APC cerebellar development as well as the development and (11–13). mutations occur infrequently in sporadic MB, although activating mutations of b-catenin are seen in up to 5% progression of human brain tumors, including MB. To identify MYC novel tumor suppressor genes involved in MB pathogenesis, of cases (14). family amplifications occur in <10% of cases weperformedanepigenome-widescreeninMBcell (15). Known genetic abnormalities explain tumorigenesis for only a lines, using 5-aza-2¶deoxycytidine to identify genes aberrantly subset of sporadic MB cases. The identification of novel genes and pathways involved in MB pathogenesis may help to explain the silenced by promoter hypermethylation. -
STYK1 Promotes Tumor Growth and Metastasis by Reducing SPINT2/HAI
Ma et al. Cell Death and Disease (2019) 10:435 https://doi.org/10.1038/s41419-019-1659-1 Cell Death & Disease ARTICLE Open Access STYK1 promotes tumor growth and metastasis by reducing SPINT2/HAI-2 expression in non-small cell lung cancer Zhiqiang Ma1,DongLiu2, Weimiao Li3,ShouyinDi1, Zhipei Zhang1,JiaoZhang1,LiqunXu4,KaiGuo1,YifangZhu1, Jing Han5,XiaofeiLi1 and Xiaolong Yan1 Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. However, the molecular mechanisms underlying NSCLC progression remains not fully understood. In this study, 347 patients with complete clinicopathologic characteristics who underwent NSCLC surgery were recruited for the investigation. We verified that elevated serine threonine tyrosine kinase 1 (STYK1) or decreased serine peptidase inhibitor Kunitz type 2 (SPINT2/HAI-2) expression significantly correlated with poor prognosis, tumor invasion, and metastasis of NSCLC patients. STYK1 overexpression promoted NSCLC cells proliferation, migration, and invasion. STYK1 also induced epithelial–mesenchymal transition by E-cadherin downregulation and Snail upregulation. Moreover, RNA-seq, quantitative polymerase chain reaction (qRT-PCR), and western blot analyses confirmed that STYK1 overexpression significantly decreased the SPINT2 level in NSCLC cells, and SPINT2 overexpression obviously reversed STYK1-mediated NSCLC progression both in vitro and in vivo. Further survival analyses showed that NSCLC patients with high STYK1 level and low SPINT2 level had the worst prognosis and survival. These results indicated that STYK1 facilitated NSCLC progression via reducing SPINT2 expression. Therefore, targeting STYK1 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; and SPINT2 may be a novel therapeutic strategy for NSCLC. Introduction and also induce rapid tumorigenesis and severe distant Serinethreoninetyrosinekinase1(STYK1),also metastasis in nude mice1. -
Hepatocyte Growth Factor Activator Inhibitor-2 Stabilizes Epcam and Maintains Epithelial Organization in the Mouse Intestine
ARTICLE https://doi.org/10.1038/s42003-018-0255-8 OPEN Hepatocyte growth factor activator inhibitor-2 stabilizes Epcam and maintains epithelial organization in the mouse intestine Makiko Kawaguchi1, Koji Yamamoto1, Naoki Takeda2, Tsuyoshi Fukushima 1, Fumiki Yamashita1, 1234567890():,; Katsuaki Sato3, Kenichiro Kitamura4, Yoshitaka Hippo5, James W. Janetka6 & Hiroaki Kataoka 1 Mutations in SPINT2 encoding the epithelial serine protease inhibitor hepatocyte growth factor activator inhibitor-2 (HAI-2) are associated with congenital tufting enteropathy. However, the functions of HAI-2 in vivo are poorly understood. Here we used tamoxifen- induced Cre-LoxP recombination in mice to ablate Spint2. Mice lacking Spint2 died within 6 days after initiating tamoxifen treatment and showed severe epithelial damage in the whole intestinal tracts, and, to a lesser extent, the extrahepatic bile duct. The intestinal epithelium showed enhanced exfoliation, villous atrophy, enterocyte tufts and elongated crypts. Orga- noid crypt culture indicated that Spint2 ablation induced Epcam cleavage with decreased claudin-7 levels and resulted in organoid rupture. These organoid changes could be rescued by addition of serine protease inhibitors aprotinin, camostat mesilate and matriptase- selective α-ketobenzothiazole as well as by co-deletion of Prss8, encoding the serine protease prostasin. These results indicate that HAI-2 is an essential cellular inhibitor for maintaining intestinal epithelium architecture. 1 Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki 8891692, Japan. 2 Center for Animal Resources and Development, Kumamoto University, Kumamoto 8600811, Japan. 3 Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki 8891692, Japan. 4 Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 4093898, Japan. -
Hepatocyte Growth Factor Activator Inhibitor Type-2 (HAI- 2)/SPINT2 Contributes to Invasive Growth of Oral Squamous Cell Carcinoma Cells
www.impactjournals.com/oncotarget/ Oncotarget, 2018, Vol. 9, (No. 14), pp: 11691-11706 Research Paper Hepatocyte growth factor activator inhibitor type-2 (HAI- 2)/SPINT2 contributes to invasive growth of oral squamous cell carcinoma cells Koji Yamamoto1,2, Makiko Kawaguchi1, Takeshi Shimomura1, Aya Izumi1, Kazuomi Konari1, Arata Honda3, Chen-Yong Lin4, Michael D. Johnson4, Yoshihiro Yamashita2, Tsuyoshi Fukushima1 and Hiroaki Kataoka1 1Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan 2Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan 3Institute of Laboratory Animals, Kyoto University Graduate School of Medicine, Kyoto, Japan 4Lambardi Comprehensive Cancer Center, Georgetown University, School of Medicine, Washington, DC, USA Correspondence to: Hiroaki Kataoka, email: [email protected] Keywords: oral squamous cell carcinoma; HAI-2; SPINT2; prostasin; HAI-1 Received: October 11, 2017 Accepted: February 01, 2018 Published: February 08, 2018 Copyright: Yamamoto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Hepatocyte growth factor activator inhibitor (HAI)-1/SPINT1 and HAI-2/SPINT2 are membrane-anchored protease inhibitors having homologous Kunitz-type inhibitor domains. They regulate membrane-anchored serine proteases, such as matriptase and prostasin. Whereas HAI-1 suppresses the neoplastic progression of keratinocytes to invasive squamous cell carcinoma (SCC) through matriptase inhibition, the role of HAI-2 in keratinocytes is poorly understood. In vitro homozygous knockout of the SPINT2 gene suppressed the proliferation of two oral SCC (OSCC) lines (SAS and HSC3) but not the growth of a non-tumorigenic keratinocyte line (HaCaT). -
Tumor Suppressor Activity and Epigenetic Inactivation of Hepatocyte Growth Factor Activator Inhibitor Type 2/SPINT2 in Papillary and Clear Cell Renal Cell Carcinoma
Research Article Tumor Suppressor Activity and Epigenetic Inactivation of Hepatocyte Growth Factor Activator Inhibitor Type 2/SPINT2 in Papillary and Clear Cell Renal Cell Carcinoma Mark R. Morris,1,2 Dean Gentle,1,2 Mahera Abdulrahman,2 Esther N. Maina,2 Kunal Gupta,2 Rosamonde E. Banks,3 Michael S. Wiesener,4 Takeshi Kishida,5 Masahiro Yao,5 Bin Teh,6 Farida Latif,1,2 and Eamonn R. Maher1,2 1Cancer Research UK Renal Molecular Oncology Group; 2Section of Medical and Molecular Genetics, Department of Pediatrics and Child Health, University of Birmingham, Birmingham, United Kingdom; 3Cancer Research UK Clinical Centre, St. James’s University Hospital, Leeds, United Kingdom; 4Department of Nephrology and Medical Intensive Care, University Clinic Charite´, Berlin, Germany; 5Yokohama City University School of Medicine, Yokohama, Japan; and 6Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan Abstract cause hereditary type 1 papillary RCC (HPRC1) and von Hippel- Following treatment with a demethylating agent, 5 of 11 renal Lindau disease, respectively (2, 3). HPRC1-associated MET cell carcinoma (RCC) cell lines showed increased expression of mutations activate MET signaling to promote cell growth and hepatocyte growth factor (HGF) activator inhibitor type 2 motility (4–7). The VHL tumor suppressor gene is inactivated by (HAI-2/SPINT2/Bikunin), a Kunitz-type protease inhibitor somatic mutation or promoter methylation in most sporadic clear that regulates HGF activity. As activating mutations in the cell RCC (8–11). However, somatic MET-activating mutations are MET proto-oncogene (the HGF receptor) cause familial RCC, uncommon (<10%) in sporadic papillary RCC and are not a feature we investigated whether HAI-2/SPINT2 might act as a RCC of sporadic clear cell RCC (3). -
Pathogenetic Role of Serine Protease Inhibitor Type 2 (SPINT2) Gene Mutations Unlikely Christian Niederwanger1, Silvia Lechner2, Lisa König3, Andreas R
Niederwanger et al. Eur J Med Res (2018) 23:13 https://doi.org/10.1186/s40001-018-0312-2 European Journal of Medical Research RESEARCH Open Access Isolated choanal and gut atresias: pathogenetic role of serine protease inhibitor type 2 (SPINT2) gene mutations unlikely Christian Niederwanger1, Silvia Lechner2, Lisa König3, Andreas R. Janecke3, Claus Pototschnig4, Beatrice Häussler5, Sabine Scholl‑Bürgi3, Thomas Müller3 and Peter Heinz‑Erian3* Abstract Background: Choanal (CA) and gastrointestinal atresias (GA) are an important feature of syndromic congenital sodium diarrhea (sCSD), a disorder recently associated with mutations in the gene for serine protease inhibitor type 2 (SPINT2). It is, however, not known whether isolated non-syndromic CA and GA themselves might result from SPINT2 mutations. Methods: We performed a prospective cohort study to investigate 19 CA and/or GA patients without diarrhea (“non- sCSD”) for potential sCSD characteristic clinical features and SPINT2 mutations. Results: We found a heterozygous SPINT2 splice mutation (c.593-1G>A), previously demonstrated in sCSD in homozygous form, in only 1 of the 19 patients of the “non-sCSD” cohort. This patient presented with isolated anal atresia and borderline low laboratory parameters of sodium balance. In the remaining 18 non-sCSD CA/GA patients investigated, SPINT2 sequence analysis and clinical markers of sodium homeostasis were normal. None of the 188 healthy controls tested in a regional Tyrolean population harbored the c.593-1G>A mutation, which is also not listed in the ExAc and gnomAD databases. Conclusions: The fnding of only one heterozygous SPINT2 mutation in 19 patients with isolated CA/GA was not statistically signifcant. -
Mechanisms of Hepatocyte Growth Factor Activation in Cancer Tissues
Cancers 2014, 6, 1890-1904; doi:10.3390/cancers6041890 OPEN ACCESS cancers ISSN 2072-6694 www.mdpi.com/journal/cancers Review Mechanisms of Hepatocyte Growth Factor Activation in Cancer Tissues Makiko Kawaguchi and Hiroaki Kataoka * Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +81-985-85-2809; Fax: +81-985-85-6003. Received: 2 July 2014; in revised form: 2 September 2014 / Accepted: 3 September 2014 / Published: 29 September 2014 Abstract: Hepatocyte growth factor/scatter factor (HGF/SF) plays critical roles in cancer progression through its specific receptor, MET. HGF/SF is usually synthesized and secreted as an inactive proform (pro-HGF/SF) by stromal cells, such as fibroblasts. Several serine proteases are reported to convert pro-HGF/SF to mature HGF/SF and among these, HGF activator (HGFA) and matriptase are the most potent activators. Increased activities of both proteases have been observed in various cancers. HGFA is synthesized mainly by the liver and secreted as an inactive pro-form. In cancer tissues, pro-HGFA is likely activated by thrombin and/or human kallikrein 1-related peptidase (KLK)-4 and KLK-5. Matriptase is a type II transmembrane serine protease that is expressed by most epithelial cells and is also synthesized as an inactive zymogen. Matriptase activation is likely to be mediated by autoactivation or by other trypsin-like proteases. Recent studies revealed that matriptase autoactivation is promoted by an acidic environment. -
The SFRP Family of WNT Inhibitors Function As Novel Tumor Suppressor Genes Epigenetically Silenced in Medulloblastoma
Oncogene (2010) 29, 3017–3024 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc SHORT COMMUNICATION The SFRP family of WNT inhibitors function as novel tumor suppressor genes epigenetically silenced in medulloblastoma PN Kongkham1,2, PA Northcott1,3, SE Croul4, CA Smith1,2, MD Taylor1,3 and JT Rutka1,2 1Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, Ontario, Canada; 2Program in Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; 3Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada and 4Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada Medulloblastoma (MB) is the most common malignant signaling is crucial for normal cerebellar development, pediatric brain tumor. Dysregulation of WNT signaling as transgenic mice with reduced WNT signaling exhibit occurs in up to 20% of cases. Using a genome-wide cerebellar aplasia (McMahon and Bradley, 1990). approach, we identified the secreted frizzled-related Turcot syndrome patients with germline adenomatous protein 1, 2 and 3 (SFRP1, SFRP2 and SFRP3) family polyposis coli (APC) gene mutation and resultant of WNT inhibitors as putative tumor suppressor genes increased WNT signaling have an increased risk of silenced by promoter region methylation in MB. SFRP1, MB (Hamilton et al., 1995). Furthermore, mutations SFRP2 and SFRP3 expression increased after 5-aza-20- affecting WNT signaling members (APC, CTNNB1, deoxycytidine treatment. SFRP1, SFRP2 and SFRP3 AXIN1 and AXIN2) are seen in 15–20% of sporadic MB methylation was identified in 23.5, 3.9 and 15.7% of cases (Eberhart et al., 2000; Baeza et al., 2003; primary MB specimens, respectively, by methylation- Thompson et al., 2006; Koch et al., 2007). -
Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease
Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................ -
Proteomic Profiling of Protease-Primed Virus-Permissive
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 17 June 2020 doi:10.20944/preprints202006.0206.v1 Proteomic profiling of protease-primed virus-permissive Caco-2 cells display abortive-interferon pathway and deregulated thromboinflammatory SERPINS Maryada Sharma* and Naresh K. Panda Department of Otolaryngology and Head & Neck Surgery Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 Abstract: Emerging paradigms in interferon (IFN) biology suggest a dynamic INF induced interactome that extends through broader Interferon Stimulated Gene (ISG)- induction, which implicates interferon- ISG coordinated cross-talk with mRNA processing, post-translational modification and metabolic processes that underlie pathological (viral, autoimmune and tumor biology) and physiological (stem cell regenerative pathways) processes. INF immune responses can also be triggered by endogenous host-derived molecules that are generated in response to cellular stress or hemostasis imbalance to establish tissue repair and regeneration in first place, however, overactivation or lack of countermeasures can result in host tissue damage. The proteases are integral to viral and tumor pathology, and importantly serine proteases TMPRSS2 and trypsin have been identified as important molecular determinants underlying COVID-19 pathology, and emergence of coronaviruses cultured in vitro, respectively. We propose that pathogen associated proteases can act as novel stress-inducers to facilitate viral- competent immunomodulation. We term it as Protease Induced Transcriptomic/ epi-Transcriptomic Reshaping (PITTR) of host cells to counter cellular stress. We present a novel experimental model and our preliminary findings of trypsin- primed Caco-2 cells (CPT) that result in translational halt comparable to cells grown under serum-starvation conditions (CSS). CPT at escalating trypsin concentration (CPT- EC) induce upregulation of selective proteins that majorly map to ribosomal, RNA transport, and spliceosome ribonucleoproteins (RNPs).