DOCSLIB.ORG

A Novel Role for TNFAIP2: Its Correlation with Invasion and Metastasis in Nasopharyngeal Carcinoma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Novel Role for TNFAIP2: Its Correlation with Invasion and Metastasis in Nasopharyngeal Carcinoma Modern Pathology (2011) 24, 175–184 & 2011 USCAP, Inc. All rights reserved 0893-3952/11 $32.00 175 A novel role for TNFAIP2: its correlation with invasion and metastasis in nasopharyngeal carcinoma Lih-Chyang Chen1, Chia-Chun Chen2, Ying Liang1, Ngan-Ming Tsang3, Yu-Sun Chang1,2 and Chuen Hsueh4 1Chang Gung Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; 2Graduate Institute of Basic Medical Sciences, Chang Gung University, Taoyuan, Taiwan; 3Department of Radiation Oncology, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan and 4Department of Pathology, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan Tumor necrosis factor alpha (TNFa) is an inflammatory cytokine that is present in the microenvironment of many tumors and is known to promote tumor progression. To examine how TNFa modulates the progression and metastasis of nasopharyngeal carcinoma, we used Affymetrix chips to identify TNFa-inducible genes that are dysregulated in this tumor. Elevated expression of TNFAIP2, which encodes TNFa-inducible protein 2 and not previously known to be associated with cancer, was found and confirmed by quantitative RT-PCR of TNFAIP2 expression in nasopharyngeal carcinoma and adjacent normal tissues. Immunohistochemical analysis showed that the TNFAIP2 protein was highly expressed in tumor cells. Analysis of 95 nasopharyngeal carcinoma biopsy specimens revealed that high TNFAIP2 expression was significantly correlated with high- level intratumoral microvessel density (P ¼ 0.005) and low distant metastasis-free survival (P ¼ 0.001). A multivariate analysis further confirmed that TNFAIP2 was an independent prognostic factor for nasopharyngeal carcinoma (P ¼ 0.002). In vitro, TNFa treatment of nasopharyngeal carcinoma HK1 cells was found to induce TNFAIP2 expression, and siRNA-based knockdown of TNFAIP2 dramatically reduced the migration and invasion of nasopharyngeal carcinoma HK1 cells. These results collectively suggest for the first time that TNFAIP2 is a cell migration-promoting protein and its expression predicts distant metastasis. Our data suggest that TNFAIP2 may serve as an independent prognostic indicator for nasopharyngeal carcinoma. Modern Pathology (2011) 24, 175–184; doi:10.1038/modpathol.2010.193; published online 5 November 2010 Keywords: metastasis; migration; nasopharyngeal carcinoma; TNFAIP2 Tumor necrosis factor alpha (TNFa), a major inflam- which TNFa increases tumor progression have not matory cytokine in the tumor microenvironment, yet been fully defined. is produced by both malignant and non-cancerous Nasopharyngeal carcinoma is a highly metastatic cells,1,2 and has been shown to mediate cancer- head and neck cancer that is relatively rare among related inflammation and promote tumor progres- Caucasians, but is common in southeastern China sion by enhancing angiogenesis and metastasis.3 and in Taiwan.8 In Hong Kong, the incidence of Increased TNFa levels in the tumor microenviron- nasopharyngeal carcinoma is as high as 20–30 per ment and plasma have been associated with poor 100 000 in men and 15–20 per 100 000 in women.8 prognosis in various cancers, including prostate According to data from the Cancer Registry of cancer,4 breast cancer,5 and nasopharyngeal Taiwan, nasopharyngeal carcinoma is the ninth carcinoma.6,7 However, the mechanisms through most common cancer, with an estimated incidence of B6 cases per 100 000 in 2002. Under the current treatment regimens, the survival rates among nasopharyngeal carcinoma patients are B92% at 1 Correspondence: Dr C Hsueh, MD, Department of Pathology, year and B50% at 5 years, with 20–25% of Chang Gung Memorial Hospital at Lin-Kou, 5, Fu-Hsing Street, patients eventually developing distant metastases.9,10 Kwei-Shan, Taoyuan 333, Taiwan. E-mail: [email protected] Nasopharyngeal carcinoma is generally sensitive Received 8 June 2010; revised 25 August 2010; accepted 30 to radiation therapy, but more advanced cases August 2010; published online 5 November 2010 may require a combination of radiotherapy and www.modernpathology.org TNFAIP2 promotes metastasis 176 L-C Chen et al chemotherapy.11 Thus, it is essential for us to previously.19 This study was reviewed and approved develop more effective diagnostic and therapeutic by the institutional review board and ethics committee strategies against nasopharyngeal carcinoma. of Chang Gung Memorial Hospital. Informed consent In an effort to clarify the underlying mechanisms was obtained from all patients. of malignancy in nasopharyngeal carcinoma, our All enrolled patients had been treated with group previously used Affymetrix-chip-based micro- definitive radiotherapy (cumulative dose of external array hybridization to identify various nasopharyn- beam radiotherapy 4R64.8 Gy). Among them, 33 geal carcinoma metastasis-associated biomarkers. patients had received additional chemotherapy in We analyzed the various TNFa-regulated genes that the Department of Medical Oncology at Chang Gung appeared to be upregulated in nasopharyngeal Memorial Hospital. Patients who presented with carcinoma tumor cells vs adjacent normal tissues, distant metastatic disease at diagnosis (M1 stage) and found differential expression of various TNFa and those who had undergone previous treatment at target genes MMP9,12 MMP12,13 MMP14,14 BIRC5,15 another institute were excluded from this study. For CXCL13,16 IL12B,17 c-FLIP,18 and thymidine phos- all enrolled patients, pathology reports were phorylase.19–21 We further showed that the upregula- obtained from the pathological database and medi- tion of thymidine phosphorylase in nasopharyngeal cal records, and the relevant slides were reviewed to carcinoma tumor cells resulted at least in part from confirm the nasopharyngeal carcinoma diagnosis cytoplasmic heterogeneous nuclear ribonucleopro- (reviews were performed by C Hsueh). Clinical data tein K (hnRNP K)-mediated stabilization of the on stage, treatment, and follow-up were collected thymidine phosphorylase mRNA.22 High levels of from hospital tumor registries and medical files. The thymidine phosphorylase and cytoplasmic hnRNP K primary end point was disease-free survival, which were significantly correlated with overall survival was calculated from the date of diagnosis to the date and distant metastasis.19 On the basis of this success, of death or last follow-up. Distant metastasis-free we have continued to search for other TNFa- survival and local recurrence-free survival were also regulated genes that could serve as potential bio- assessed. The time to local recurrence or distant markers for nasopharyngeal carcinoma prognosis. metastasis was calculated by using the date on TNFAIP2 is also a TNFa-regulated gene that is which the local recurrence or distant metastasis was expressed in endothelial cells,23 peripheral blood detected as the end point. Patients who died with- monocytes,24 and mature sperm.24 Here we investi- out local recurrence or distant metastasis were gated TNFAIP2, which is found to be highly omitted from our analyses of disease-free survival, expressed at both the mRNA and protein levels in local recurrence-free survival, and distant metasta- nasopharyngeal carcinoma tumor cells vs adjacent sis-free survival. normal tissues. TNFAIP2 encodes a protein whose precise function is not known, but appears to be Affymetrix Microarray Analysis involved in endothelial capillary tube formation in vitro.23 Although TNFAIP2 has been classified as RNA samples from nasopharyngeal carcinoma an angiogenic factor,23 its function and significance tissues were isolated using the TRIzol reagent in tumor development have not previously been (Invitrogen, Carlsbad, CA, USA). The biotinylated determined. Here, we show for the first time that oligonucleotide was hybridized to the Human increased expression of TNFAIP2 is significantly Genome U133 Plus 2.0 Array (Affymetrix, Santa correlated with shorter distant metastasis-free sur- Clara, CA, USA) by the National Yang-Ming Uni- vival in nasopharyngeal carcinoma patients, and versity Genomics Center (Taiwan), following the that TNFAIP2 promotes the migration and invasion manufacturer’s instructions. The microarray data of nasopharyngeal carcinoma cells in vitro. These were analyzed using the GeneSpring version GX results suggest that TNFAIP2 may serve as a 7.31 software package (Silcogenetics, Redwood, CA, potential diagnostic and independent prognostic USA). The relative expression level of each gene was marker for nasopharyngeal carcinoma. calculated as the ratio of the average hybridization intensity from nine individual nasopharyngeal carcinoma tissues vs that from a pool of the Materials and methods corresponding adjacent non-tumor tissues. Patients, Clinical Staging, Treatment, and Assessment of Clinical Outcome Immunohistochemical Staining Analysis The utilized retrospective cohort comprised 95 naso- Immunohistochemical analyses were performed pharyngeal carcinoma patients who had been ad- using an automatic immunohistochemical staining mitted to Chang Gung Memorial Hospital at Lin-Kou device according to the manufacturer’s instructions from 1990 to 2006. AJCC stage, T stage, and N stage (Bond-max Automated Immunostainer; Vision Bio- were defined according to the 2002 cancer-staging Systems, Melbourne, Australia). Tissue sections system revised by the American Joint Committee on were retrieved using Bond Epitope Retrieval Cancer. Histological typing was performed according Solution 1 (Vision BioSystems) and stained with to the WHO classification criteria,
Load more

Recommended publications
  • Peripheral Glycolysis in Neurodegenerative Diseases
    International Journal of Molecular Sciences Review Peripheral Glycolysis in Neurodegenerative Diseases Simon M. Bell * , Toby Burgess, James Lee, Daniel J. Blackburn, Scott P. Allen and Heather Mortiboys Sheffield Institute for Translational Neurosciences, University of Sheffield, Sheffield S10 2HQ, UK; t.burgess@sheffield.ac.uk (T.B.); james.lee@sheffield.ac.uk (J.L.); d.blackburn@sheffield.ac.uk (D.J.B.); s.p.allen@sheffield.ac.uk (S.P.A.); [email protected] (H.M.) * Correspondence: s.m.bell@sheffield.ac.uk; Tel.: +44-(0)-114-2222273 Received: 31 October 2020; Accepted: 21 November 2020; Published: 24 November 2020 Abstract: Neurodegenerative diseases are a group of nervous system conditions characterised pathologically by the abnormal deposition of protein throughout the brain and spinal cord. One common pathophysiological change seen in all neurodegenerative disease is a change to the metabolic function of nervous system and peripheral cells. Glycolysis is the conversion of glucose to pyruvate or lactate which results in the generation of ATP and has been shown to be abnormal in peripheral cells in Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Changes to the glycolytic pathway are seen early in neurodegenerative disease and highlight how in multiple neurodegenerative conditions pathology is not always confined to the nervous system. In this paper, we review the abnormalities described in glycolysis in the three most common neurodegenerative diseases. We show that in all three diseases glycolytic changes are seen in fibroblasts, and red blood cells, and that liver, kidney, muscle and white blood cells have abnormal glycolysis in certain diseases.
    [Show full text]
  • Hematology Test Requisition
    GENETICS AND GENOMICS DIAGNOSTIC LABORATORY Mailing Address: For local courier service and/or inquiries, please contact 513-636-4474 • Fax: 513-636-4373 3333 Burnet Avenue, Room R1042 www.cincinnatichildrens.org/moleculargenetics • Email: [email protected] Cincinnati, OH 45229 HEMATOLOGY TEST REQUISITION All Information Must Be Completed Before Sample Can Be Processed PATIENT INFORMATION ETHNIC/RACIAL BACKGROUND (Choose All) Patient Name: _____________________, ___________________, ________ European American (White) African-American (Black) Last First MI Native American or Alaskan Asian-American Address: _____________________________________________________ Pacific Islander Ashkenazi Jewish ancestry _____________________________________________________ Latino-Hispanic _____________________________________________ Home Phone: _________________________________________________ (specify country/region of origin) MR# __________________ Date of Birth ________ /________ / ________ Other ____________________________________________________ (specify country/region of origin) Sex: Male Female BILLING INFORMATION REFERRING PHYSICIAN o REFERRING INSTITUTION Physician Name (print): _________________________________________ Institution: ____________________________________________________ Address: ____________________________________________________ Address: _____________________________________________________ Phone: ( _______ ) _______________ Fax: ( _______ ) _______________ City/State/Zip: _________________________________________________
    [Show full text]
  • PIM2-Mediated Phosphorylation of Hexokinase 2 Is Critical for Tumor Growth and Paclitaxel Resistance in Breast Cancer
    Oncogene (2018) 37:5997–6009 https://doi.org/10.1038/s41388-018-0386-x ARTICLE PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer 1 1 1 1 1 2 2 3 Tingting Yang ● Chune Ren ● Pengyun Qiao ● Xue Han ● Li Wang ● Shijun Lv ● Yonghong Sun ● Zhijun Liu ● 3 1 Yu Du ● Zhenhai Yu Received: 3 December 2017 / Revised: 30 May 2018 / Accepted: 31 May 2018 / Published online: 9 July 2018 © The Author(s) 2018. This article is published with open access Abstract Hexokinase-II (HK2) is a key enzyme involved in glycolysis, which is required for breast cancer progression. However, the underlying post-translational mechanisms of HK2 activity are poorly understood. Here, we showed that Proviral Insertion in Murine Lymphomas 2 (PIM2) directly bound to HK2 and phosphorylated HK2 on Thr473. Biochemical analyses demonstrated that phosphorylated HK2 Thr473 promoted its protein stability through the chaperone-mediated autophagy (CMA) pathway, and the levels of PIM2 and pThr473-HK2 proteins were positively correlated with each other in human breast cancer. Furthermore, phosphorylation of HK2 on Thr473 increased HK2 enzyme activity and glycolysis, and 1234567890();,: 1234567890();,: enhanced glucose starvation-induced autophagy. As a result, phosphorylated HK2 Thr473 promoted breast cancer cell growth in vitro and in vivo. Interestingly, PIM2 kinase inhibitor SMI-4a could abrogate the effects of phosphorylated HK2 Thr473 on paclitaxel resistance in vitro and in vivo. Taken together, our findings indicated that PIM2 was a novel regulator of HK2, and suggested a new strategy to treat breast cancer. Introduction ATP molecules.
    [Show full text]
  • Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory
    University of Kentucky UKnowledge Rehabilitation Sciences Faculty Publications Rehabilitation Sciences 4-2017 Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice Maria C. Seleme University of Alabama at Birmingham Kate Kosmac University of Kentucky, [email protected] Stipan Jonjic University of Rejika, Croatia William J. Britt University of Alabama at Birmingham Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/rehabsci_facpub Part of the Immunology and Infectious Disease Commons, Rehabilitation and Therapy Commons, and the Virology Commons Repository Citation Seleme, Maria C.; Kosmac, Kate; Jonjic, Stipan; and Britt, William J., "Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice" (2017). Rehabilitation Sciences Faculty Publications. 82. https://uknowledge.uky.edu/rehabsci_facpub/82 This Article is brought to you for free and open access by the Rehabilitation Sciences at UKnowledge. It has been accepted for inclusion in Rehabilitation Sciences Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact [email protected]. Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice Notes/Citation Information Published in Journal of Virology, v. 91, issue 8, e01983-16, p. 1-22. Copyright © 2017 American Society for Microbiology. All Rights Reserved. The opc yright holder has granted the permission for posting the article here.
    [Show full text]
  • Insulin Controls Triacylglycerol Synthesis Through Control of Glycerol Metabolism and Despite Increased Lipogenesis
    nutrients Article Insulin Controls Triacylglycerol Synthesis through Control of Glycerol Metabolism and Despite Increased Lipogenesis Ana Cecilia Ho-Palma 1,2 , Pau Toro 1, Floriana Rotondo 1, María del Mar Romero 1,3,4, Marià Alemany 1,3,4, Xavier Remesar 1,3,4 and José Antonio Fernández-López 1,3,4,* 1 Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; [email protected] (A.C.H.-P.); [email protected] (P.T.); fl[email protected] (F.R.); [email protected] (M.d.M.R.); [email protected] (M.A.); [email protected] (X.R.) 2 Faculty of Medicine, Universidad Nacional del Centro del Perú, 12006 Huancayo, Perú 3 Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain 4 Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBER-OBN), 08028 Barcelona, Spain * Correspondence: [email protected]; Tel: +34-93-4021546 Received: 7 February 2019; Accepted: 22 February 2019; Published: 28 February 2019 Abstract: Under normoxic conditions, adipocytes in primary culture convert huge amounts of glucose to lactate and glycerol. This “wasting” of glucose may help to diminish hyperglycemia. Given the importance of insulin in the metabolism, we have studied how it affects adipocyte response to varying glucose levels, and whether the high basal conversion of glucose to 3-carbon fragments is affected by insulin. Rat fat cells were incubated for 24 h in the presence or absence of 175 nM insulin and 3.5, 7, or 14 mM glucose; half of the wells contained 14C-glucose. We analyzed glucose label fate, medium metabolites, and the expression of key genes controlling glucose and lipid metabolism.
    [Show full text]
  • Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension
    Journal of Clinical Medicine Article Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension Mathews Valuparampil Varghese y, Joel James y, Cody A Eccles, Maki Niihori, Olga Rafikova * and Ruslan Rafikov * Department of Medicine, Division of Endocrinology, University of Arizona College of Medicine, Tucson, AZ 85721, USA; [email protected] (M.V.V.); [email protected] (J.J.); [email protected] (C.A.E.); [email protected] (M.N.) * Correspondence: orafi[email protected] (O.R.); ruslanrafi[email protected] (R.R.); Tel.: +1-520-626-1303 (O.R.); +1-520-626-6092 (R.R.) These authors contributed equally to this work. y Received: 13 December 2019; Accepted: 4 February 2020; Published: 6 February 2020 Abstract: Vascular remodeling is considered a key event in the pathogenesis of pulmonary arterial hypertension (PAH). However, mechanisms of gaining the proliferative phenotype by pulmonary vascular cells are still unresolved. Due to well-established pyruvate dehydrogenase (PDH) deficiency in PAH pathogenesis, we hypothesized that the activation of another branch of pyruvate metabolism, anaplerosis, via pyruvate carboxylase (PC) could be a key contributor to the metabolic reprogramming of the vasculature. In sugen/hypoxic PAH rats, vascular proliferation was found to be accompanied by increased activation of Akt signaling, which upregulated membrane Glut4 translocation and caused upregulation of hexokinase and pyruvate kinase-2, and an overall increase in the glycolytic flux. Decreased PDH activity and upregulation of PC shuttled more pyruvate to oxaloacetate. This results in the anaplerotic reprogramming of lung vascular cells and their subsequent proliferation. Treatment of sugen/hypoxia rats with the PC inhibitor, phenylacetic acid 20 mg/kg, starting after one week from disease induction, significantly attenuated right ventricular systolic pressure, Fulton index, and pulmonary vascular cell proliferation.
    [Show full text]
  • Gastrointestinal Stromal Tumor
    저작자표시-비영리-변경금지 2.0 대한민국 이용자는 아래의 조건을 따르는 경우에 한하여 자유롭게 l 이 저작물을 복제, 배포, 전송, 전시, 공연 및 방송할 수 있습니다. 다음과 같은 조건을 따라야 합니다: 저작자표시. 귀하는 원저작자를 표시하여야 합니다. 비영리. 귀하는 이 저작물을 영리 목적으로 이용할 수 없습니다. 변경금지. 귀하는 이 저작물을 개작, 변형 또는 가공할 수 없습니다. l 귀하는, 이 저작물의 재이용이나 배포의 경우, 이 저작물에 적용된 이용허락조건 을 명확하게 나타내어야 합니다. l 저작권자로부터 별도의 허가를 받으면 이러한 조건들은 적용되지 않습니다. 저작권법에 따른 이용자의 권리는 위의 내용에 의하여 영향을 받지 않습니다. 이것은 이용허락규약(Legal Code)을 이해하기 쉽게 요약한 것입니다. Disclaimer Clinicopathologic features and molecular characteristics of glucose metabolism contributing to 18F-fluorodeoxyglucose uptake in gastrointestinal stromal tumor Min-Hee Cho Department of Medical Science The Graduate School, Yonsei University Clinicopathologic features and molecular characteristics of glucose metabolism contributing to 18F-fluorodeoxyglucose uptake in gastrointestinal stromal tumor Directed by Professor Hoguen Kim The Master's Thesis submitted to the Department of Medical Science, the Graduate School of Yonsei University in partial fulfillment of the requirements for the degree of Master of Medical Science Min-Hee Cho December 2015 This certifies that the Master's Thesis of Min-Hee Cho is approved. _________________________________ Thesis Supervisor: Hoguen Kim _________________________________ Thesis Committee Member#1: Kyung-Sup Kim _________________________________ Thesis Committee Member#2: Jae-Ho Cheong The Graduate School Yonsei University December 2015 ACKNOWLEDGEMENTS 아직도 모르는 것이 너무 많은데 어느덧 졸업을 앞두고 있으니, 기쁘지만 걱정스러운 마음이 더 큽니다. 시행착오 속에서 제가 학위논문을 마무리할 수 있었던 이유는, 학위기간 중 저를 응원해주고 도와주셨던 분들 덕분이라고 생각합니다. 먼저 저를 제자로 받아주시고, 많은 성과를 내지 못했는데 끝까지 기다려주시고 지도해주신 김호근 교수님께 진심으로 감사 드립니다.
    [Show full text]
  • Metabolic Characteristics of Solid Pseudopapillary Neoplasms of the Pancreas: Their Relationships with High Intensity 18F-FDG PET Images
    www.impactjournals.com/oncotarget/ Oncotarget, 2018, Vol. 9, (No. 15), pp: 12009-12019 Research Paper Metabolic characteristics of solid pseudopapillary neoplasms of the pancreas: their relationships with high intensity 18F-FDG PET images Minhee Park1,*, Ho Kyoung Hwang2,4,*, Mijin Yun3,4, Woo Jung Lee2,4, Hoguen Kim1 and Chang Moo Kang2,4 1Departments of Pathology and BK21 PLUS for Medical Science, Yonsei University College of Medicine, Seoul, Korea 2Department of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea 3Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, Korea 4Pancreatobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, Korea *These authors contributed equally to this work Correspondence to: Hoguen Kim, email: [email protected] Chang Moo Kang, email: [email protected] Keywords: solid pseudopapillary neoplasm; metabolomics; metabolism; 18F-FDG-PET; pancreatectomy Received: October 05, 2017 Accepted: November 14, 2017 Published: January 03, 2018 Copyright: Park 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 Objective: We aimed to investigate the metabolic characteristics of Solid pseudopapillary neoplasms (SPNs) in relation signal intensities on 18F-FDG PET scans. Summary Background Data: SPNs of the pancreas commonly show high uptake of 18F-FDG. However, the metabolic characteristics underlying the high 18F-FDG uptake in SPNs are not well characterized. Materials and Methods: mRNA expressions for glucose metabolism were analyzed in five SPNs, five pancreatic ductal adenocarcinomas (PCAs), and paired normal pancreatic tissues.
    [Show full text]
  • Inborn Defects in the Antioxidant Systems of Human Red Blood Cells
    Free Radical Biology and Medicine 67 (2014) 377–386 Contents lists available at ScienceDirect Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed Review Article Inborn defects in the antioxidant systems of human red blood cells Rob van Zwieten a,n, Arthur J. Verhoeven b, Dirk Roos a a Laboratory of Red Blood Cell Diagnostics, Department of Blood Cell Research, Sanquin Blood Supply Organization, 1066 CX Amsterdam, The Netherlands b Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands article info abstract Article history: Red blood cells (RBCs) contain large amounts of iron and operate in highly oxygenated tissues. As a result, Received 16 January 2013 these cells encounter a continuous oxidative stress. Protective mechanisms against oxidation include Received in revised form prevention of formation of reactive oxygen species (ROS), scavenging of various forms of ROS, and repair 20 November 2013 of oxidized cellular contents. In general, a partial defect in any of these systems can harm RBCs and Accepted 22 November 2013 promote senescence, but is without chronic hemolytic complaints. In this review we summarize the Available online 6 December 2013 often rare inborn defects that interfere with the various protective mechanisms present in RBCs. NADPH Keywords: is the main source of reduction equivalents in RBCs, used by most of the protective systems. When Red blood cells NADPH becomes limiting, red cells are prone to being damaged. In many of the severe RBC enzyme Erythrocytes deficiencies, a lack of protective enzyme activity is frustrating erythropoiesis or is not restricted to RBCs. Hemolytic anemia Common hereditary RBC disorders, such as thalassemia, sickle-cell trait, and unstable hemoglobins, give G6PD deficiency Favism rise to increased oxidative stress caused by free heme and iron generated from hemoglobin.
    [Show full text]
  • ZBTB7A Acts As a Tumor Suppressor Through the Transcriptional Repression of Glycolysis
    Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press ZBTB7A acts as a tumor suppressor through the transcriptional repression of glycolysis Xue-Song Liu,1 Jenna E. Haines,1 Elie K. Mehanna,1 Matthew D. Genet,1 Issam Ben-Sahra,1 John M. Asara,2 Brendan D. Manning,1 and Zhi-Min Yuan1 1Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA; 2Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA Elevated glycolysis is a common metabolic trait of cancer, but what drives such metabolic reprogramming remains incompletely clear. We report here a novel transcriptional repressor-mediated negative regulation of glycolysis. ZBTB7A, a member of the POK (POZ/BTB and Kruppel)€ transcription repressor family, directly binds to the promoter and represses the transcription of critical glycolytic genes, including GLUT3, PFKP, and PKM. Analysis of The Cancer Genome Atlas (TCGA) data sets reveals that the ZBTB7A locus is frequently deleted in many human tumors. Significantly, reduced ZBTB7A expression correlates with up-regulation of the glycolytic genes and poor survival in colon cancer patients. Remarkably, while ZBTB7A-deficient tumors progress exceedingly fast, they exhibit an unusually heightened sensitivity to glycolysis inhibition. Our study uncovers a novel tumor suppressor role of ZBTB7A in directly suppressing glycolysis. [Keywords: glycolysis; tumor suppressor; ZBTB7A; GLUT3; PFKP; PKM] Supplemental material is available for this article. Received May 21, 2014; revised version accepted August 8, 2014. Metabolic reprograming is a hallmark of human cancer phosphorylation by inducing the expression of synthesis and accelerated aerobic glycolysis (or the Warburg effect) of cytochrome c oxidase (SCO2) and the TP53-induced and is frequently observed in multiple types of cancer glycolysis and apoptosis regulator (TIGAR) that inhibits (Hanahan and Weinberg 2011).
    [Show full text]
  • Glucokinase Intrinsically Regulates Glucose Sensing and Glucagon
    www.nature.com/scientificreports OPEN Glucokinase intrinsically regulates glucose sensing and glucagon secretion in pancreatic alpha cells Tilo Moede1*, Barbara Leibiger1, Pilar Vaca Sanchez1, Elisabetta Daré1, Martin Köhler1, Thusitha P. Muhandiramlage1, Ingo B. Leibiger1,2 & Per‑Olof Berggren1,2 The secretion of glucagon by pancreatic alpha cells is regulated by a number of external and intrinsic factors. While the electrophysiological processes linking a lowering of glucose concentrations to an increased glucagon release are well characterized, the evidence for the identity and function of the glucose sensor is still incomplete. In the present study we aimed to address two unsolved problems: (1) do individual alpha cells have the intrinsic capability to regulate glucagon secretion by glucose, and (2) is glucokinase the alpha cell glucose sensor in this scenario. Single cell RT‑PCR was used to confrm that glucokinase is the main glucose‑phosphorylating enzyme expressed in rat pancreatic alpha cells. Modulation of glucokinase activity by pharmacological activators and inhibitors led to a lowering or an increase of the glucose threshold of glucagon release from single alpha cells, measured by TIRF microscopy, respectively. Knockdown of glucokinase expression resulted in a loss of glucose control of glucagon secretion. Taken together this study provides evidence for a crucial role of glucokinase in intrinsic glucose regulation of glucagon release in rat alpha cells. Secretion of the blood glucose elevating hormone glucagon by pancreatic alpha cells increases rapidly when blood glucose concentration drops. An increase in glucagon leads to stimulation of glucose production by the liver and thereby an increase in blood glucose levels 1,2.
    [Show full text]
  • Cytotoxic Activity of Deferiprone, Maltol and Related Hydroxyketones Against Human Tumor Cell Lines
    ANTICANCER RESEARCH 24: 755-762 (2004) Cytotoxic Activity of Deferiprone, Maltol and Related Hydroxyketones against Human Tumor Cell Lines EIJI YASUMOTO1, KENSUKE NAKANO1, TOHRU NAKAYACHI1, SUFI REZA MD. MORSHED1, KEN HASHIMOTO1, HIROTAKA KIKUCHI2, HIROFUMI NISHIKAWA2, MASAMI KAWASE3 and HIROSHI SAKAGAMI1 1Department of Dental Pharmacology and 2Department of Endodontics, Meikai University School of Dentistry, Sakado, Saitama; 3Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan Abstract. Hydroxyketone chelators, deferiprone (HK1), maltol essential element for tumor cell growth and DNA (HK3) and their related compounds (HK2, 4-8), were replication. Previous studies have shown that various iron characterized for their cytotoxic profiles against oral human chelators, such as deferoxamine, deferiprone and hinokitiol, normal and tumor cells. Most hydroxyketones except HK6 showed are able to inhibit DNA synthesis and tumor cell relatively higher tumor-specific cytotoxicity. Deferiprone (HK1), proliferation in a number of hepatoma, teratocarcinoma F9 which showed the highest tumor specificity, had 10 times higher (2, 3) and neuroblastoma cell lines (4). The iron chelators cytotoxicity than maltol (HK3) in both human promyelocytic have also been reported to induce apoptosis in proliferating leukemia HL-60 and human oral squamous cell carcinoma lymphocytes and leukemic cells by iron deprivation (5). HSC-2 cell lines. The cytotoxic activity of HK1 against HL-60 and Hinokitiol, Á-thujaplicin and ‚-dolabrin showed strong HSC-2 cells was reduced in the presence of FeCl3, while that of cytotoxic activities against stomach cancer KATO-III and HK3 was significantly increased by FeCl3. Agarose gel Ehrlich's ascites carcinoma (6). These molecules have been electrophoresis showed that HK1 induced internucleosomal DNA proved to be suitable ligands for metal ions (Fe3+, Al3+) fragmentation in HL-60 cells, but the addition of FeCl3 inhibited and have been occasionally used in chelation therapy (7, 8).
    [Show full text]