{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:22:58Z","timestamp":1790104978712,"version":"4.0.1"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,3]],"date-time":"2022-05-03T00:00:00Z","timestamp":1651536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>G protein-coupled receptor 56 (GPR56\/ADGRG1) is an adhesion GPCR with an essential role in brain development and cancer. Elevated expression of GPR56 was observed in the clinical specimens of Glioblastoma (GBM), a highly invasive primary brain tumor. However, we found the expression to be\u00a0variable across the specimens, presumably due to the intratumor heterogeneity of GBM.\u00a0Therefore, we re-examined GPR56 expression in public domain spatial gene expression data and single-cell expression data for GBM, which revealed that GPR56 expression was high in cellular tumors, infiltrating tumor cells, and proliferating cells, low in microvascular proliferation and peri-necrotic areas of the tumor, especially in hypoxic mesenchymal-like cells. To gain a better understanding of the consequences of GPR56 downregulation in tumor cells and other molecular changes associated with it, we generated a sh-RNA-mediated GPR56 knockdown in the GBM cell line U373 and performed transcriptomics, proteomics, and phospho-proteomics analysis. Our analysis revealed enrichment of gene signatures, pathways, and phosphorylation of proteins potentially associated with mesenchymal (MES) transition in the tumor and concurrent increase in cell invasion and migration behavior of the GPR56 knockdown GBM cells. Interestingly, our analysis also showed elevated expression of Transglutaminase 2 (TG2) - a known interactor of GPR56, in the knockdown cells. The inverse expression of GPR56 and TG2 was also observed in intratumoral, spatial gene expression data for GBM and in GBM cell lines cultured <jats:italic>in vitro<\/jats:italic> under hypoxic conditions. Integrating all these observations, we propose a putative functional link between the inverse expression of the two proteins, the hypoxic niche and the mesenchymal status in the tumor. Hypoxia-induced downregulation of GPR56 and activation of TG2 may result in a network of molecular events that contribute to the mesenchymal transition of GBM cells, and we propose a putative model to explain this functional and regulatory relationship of the two proteins.<\/jats:p>","DOI":"10.3389\/fonc.2022.841890","type":"journal-article","created":{"date-parts":[[2022,5,3]],"date-time":"2022-05-03T06:14:17Z","timestamp":1651558457000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Multi-Omics Analysis of Glioblastoma and Glioblastoma Cell Line: Molecular Insights Into the Functional Role of GPR56 and TG2 in Mesenchymal Transition"],"prefix":"10.3389","volume":"12","author":[{"given":"Raksha A.","family":"Ganesh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranali","family":"Sonpatki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Naik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arivusudar Everad","family":"John","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gajanan","family":"Sathe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akhila","family":"Lakshmikantha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komal Prasad","family":"Chandrachari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Kn\u00e4uper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Aeschlimann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishnan","family":"Venkatraaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nameeta","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Sirdeshmukh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.16669","article-title":"Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma a Randomized Clinical Trial","volume":"314","author":"Stupp","year":"2015","journal-title":"JAMA - J Am Med Assoc"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254257","article-title":"Single-Cell RNA-Seq Highlights Intratumoral Heterogeneity in Primary Glioblastoma","volume":"344","author":"Patel","year":"2014","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.ccr.2009.12.020","article-title":"Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1","volume":"17","author":"Verhaak","year":"2010","journal-title":"Cancer Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.ccell.2017.06.003","article-title":"Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates With Immunological Changes in the Microenvironment","volume":"32","author":"Wang","year":"2017","journal-title":"Cancer Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/glia.21165","article-title":"Molecular Subclassification of Diffuse Gliomas: Seeing Order in the Chaos","volume":"59","author":"Huse","year":"2011","journal-title":"Glia"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/PPO.0b013e3182431c57","article-title":"Studying a Complex Tumor: Potential and Pitfalls","volume":"18","author":"Zheng","year":"2012","journal-title":"Cancer J"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf2666","article-title":"An Anatomic Transcriptional Atlas of Human Glioblastoma","volume":"360","author":"Puchalski","year":"2018","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.06.024","article-title":"An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma","volume":"178","author":"Neftel","year":"2019","journal-title":"Cell"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0329","article-title":"The Phenotypes of Proliferating Glioblastoma Cells Reside on a Single Axis of Variation","volume":"9","author":"Wang","year":"2019","journal-title":"Cancer Discov"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010617-052933","article-title":"Adhesion G Protein\u2013Coupled Receptors as Drug Targets","volume":"58","author":"Purcell","year":"2018","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2019.02.003","article-title":"Adhesion G Protein-Coupled Receptors as Drug Targets for Neurological Diseases","volume":"40","author":"Folts","year":"2019","journal-title":"Trends Pharmacol Sci"},{"key":"B12","doi-asserted-by":"publisher","first-page":"re3","DOI":"10.1126\/scisignal.2003825","article-title":"Sticky Signaling - Adhesion Class G Protein-Coupled Receptors Take the Stage","volume":"6","author":"Langenhan","year":"2013","journal-title":"Sci Signal"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1104821108","article-title":"G Protein-Coupled Receptor 56 and Collagen III, a Receptor-Ligand Pair, Regulates Cortical Development and Lamination","volume":"108","author":"Luo","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092780","article-title":"R EPORTS G Protein \u2013 Coupled Receptor \u2013 Dependent Development of Human Frontal Cortex","volume":"303","author":"Piao","year":"2004","journal-title":"Science"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/eLife.33385","article-title":"Microglial Transglutaminase-2 Drives Myelination and Myelin Repair via GPR56\/ADGRG1 in Oligodendrocyte Precursor Cells","volume":"7","author":"Giera","year":"2018","journal-title":"Elife"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20161714","article-title":"GPR56\/ADG RG1 Regulates Development and Maintenance of Peripheral Myelin","volume":"215","author":"Ackerman","year":"2018","journal-title":"J Exp Med"},{"key":"B17","doi-asserted-by":"publisher","first-page":"6122","DOI":"10.1038\/ncomms7122","article-title":"The Adhesion GPCR Gpr56 Regulates Oligodendrocyte Development via Interactions With Ga12\/13and RhoA","volume":"6","author":"Ackerman","year":"2015","journal-title":"Nat Commun"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-07-0066","article-title":"Orphan G Protein-Coupled Receptor GPR56 Plays a Role in Cell Transformation and Tumorigenesis Involving the Cell Adhesion Pathway","volume":"6","author":"Ke","year":"2007","journal-title":"Mol Cancer Ther"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4149\/neo_2017_104","article-title":"Expression of Orphan GPR56 Correlates With Tumor Progression in Human Epithelial Ovarian Cancer","volume":"64","author":"Liu","year":"2017","journal-title":"Neoplasma"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208395","article-title":"GPR56 Is a GPCR That Is Overexpressed in Gliomas and Functions in Tumor Cell Adhesion","volume":"24","author":"Shashidhar","year":"2005","journal-title":"Oncogene"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2005.03.018","article-title":"Differential Expression of G-Protein Coupled Receptor 56 in Human Esophageal Squamous Cell Carcinoma","volume":"233","author":"Sud","year":"2006","journal-title":"Cancer Lett"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7402","article-title":"Cell-Surface Markers for Colon Adenoma and Adenocarcinoma","volume":"7","author":"Sewda","year":"2016","journal-title":"Oncotarget"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.174458","article-title":"Heparin Interacts With the Adhesion GPCR GPR56, Reduces Receptor Shedding, and Promotes Cell Adhesion and Motility","volume":"129","author":"Chiang","year":"2016","journal-title":"J Cell Sci"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3892\/or.2018.6582","article-title":"GPR56 Promotes Proliferation of Colorectal Cancer Cells and Enhances Metastasis via Epithelial-Mesenchymal Transition Through PI3K\/AKT Signaling Activation","volume":"40","author":"Ji","year":"2018","journal-title":"Oncol Rep"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1182-09.2009","article-title":"GPR56-Regulated Granule Cell Adhesion Is Essential for Rostral Cerebellar Development","volume":"29","author":"Koirala","year":"2009","journal-title":"J Neurosci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.10.083","article-title":"GPR56\/ ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma","volume":"21","author":"Moreno","year":"2017","journal-title":"Cell Rep"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-4543","article-title":"GPR56 Regulates VEGF Production and Angiogenesis During Melanoma Progression","volume":"71","author":"Yang","year":"2011","journal-title":"Cancer Res"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18632\/oncotarget.16506","article-title":"The GProtein Coupled Receptor 56, Expressed in Colonic Stem and Cancer Cells, Binds Progastrin to Promote Proliferation and Carcinogenesis","volume":"8","author":"Jin","year":"2017","journal-title":"Oncotarget"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1268","article-title":"GPR56 Inhibits Melanoma Growth by Internalizing and Degrading Its Ligand TG2","volume":"74","author":"Yang","year":"2014","journal-title":"Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602681103","article-title":"GPR56, an Atypical G Protein-Coupled Receptor, Binds Tissue Transglutaminase, TG2, and Inhibits Melanoma Tumor Growth and Metastasis","volume":"103","author":"Xu","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/B978-0-12-394305-7.00001-X","article-title":"Cellular Functions of Tissue Transglutaminase","volume":"294","author":"Nurminskaya","year":"2012","journal-title":"Int Rev Cell Mol Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/MC.22986","article-title":"Transglutaminase 2 Takes Center Stage as a Cancer Cell Survival Factor and Therapy Target","volume":"58","author":"Eckert","year":"2019","journal-title":"Mol Carcinog"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-0388","article-title":"Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C\/Ebpb Signaling","volume":"77","author":"Yin","year":"2017","journal-title":"Cancer Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M111.013565","article-title":"LCMS\/ MS Analysis of Differentially Expressed Glioblastoma Membrane Proteome Reveals Altered Calcium Signaling and Other Protein Groups of Regulatory Functions","volume":"11","author":"Polisetty","year":"2012","journal-title":"Mol Cell Proteomics"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep26882","article-title":"Microsomal Membrane Proteome of Low Grade Diffuse Astrocytomas: Differentially Expressed Proteins and Candidate Surveillance Biomarkers","volume":"6","author":"Polisetty","year":"2016","journal-title":"Sci Rep"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2-DDCT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"B37","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast Universal RNA-Seq Aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq033","article-title":"BEDTools: A Flexible Suite of Utilities for Comparing Genomic Features","volume":"26","author":"Quinlan","year":"2010","journal-title":"Bioinformatics"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1101\/GR.772403","article-title":"PANTHER: A Library of Protein Families and Subfamilies Indexed by Function","volume":"13","author":"Thomas","year":"2003","journal-title":"Genome Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp1019","article-title":"PANTHER Version 7: Improved Phylogenetic Trees, Orthologs and Collaboration With the Gene Ontology Consortium","volume":"38","author":"Mi","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"B41","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-16104-4_14","article-title":"THP-1 and U937 Cells","volume-title":"The Impact of Food Bioactives on Health: In Vitro and Ex Vivo Models","author":"Chanput","year":"2015"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/6031486","article-title":"Monocyte Differentiation Towards Protumor Activity Does Not Correlate With M1 or M2 Phenotypes","volume":"2016","author":"Chimal-Ram\u0131\u0301rez","year":"2016","journal-title":"J Immunol Res"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-1776","article-title":"Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-2 Fusion cDNA for Cancer Gene Immunotherapy","volume":"64","author":"Stagg","year":"2004","journal-title":"Cancer Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20112746","article-title":"Proneural- Mesenchymal Transition: Phenotypic Plasticity to Acquire Multitherapy Resistance in Glioblastoma","volume":"20","author":"Fedele","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-01178-9","article-title":"ARTICLE EMTome: A Resource for Pan-Cancer Analysis of Epithelial-Mesenchymal Transition Genes and Signatures","volume":"124","author":"Vasaikar","year":"2021","journal-title":"Br J Cancer"},{"key":"B46","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/J.CANLET.2019.05.010","article-title":"The ATP-Binding Cassette Transporter ABCF1 Is a Hepatic Oncofetal Protein That Promotes Chemoresistance, EMT and Cancer Stemness in Hepatocellular Carcinoma","volume":"457","author":"Fung","year":"2019","journal-title":"Cancer Lett"},{"key":"B47","doi-asserted-by":"publisher","first-page":"14379","DOI":"10.1038\/S41598-018-32796-2","article-title":"Ahnak Promotes Tumor Metastasis Through Transforming Growth Factor-b-Mediated Epithelial-Mesenchymal Transition","volume":"8","author":"Sohn","year":"2018","journal-title":"Sci Rep"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.147922","article-title":"\u201cStandby\u201d EMT and \u201cImmune Cell Trapping\u201d Structure as Novel Mechanisms for Limiting Neuronal Damage After CNS Injury","volume":"9","author":"Cha","year":"2014","journal-title":"Neural Regener Res"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.18632\/ONCOTARGET.16608","article-title":"Cofilin 1 Induces the Epithelial-Mesenchymal Transition of Gastric Cancer Cells by Promoting Cytoskeletal Rearrangement","volume":"8","author":"Haibo","year":"2017","journal-title":"Oncotarget"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/JCP.29107","article-title":"CSE1L Silence Inhibits the Growth and Metastasis in Gastric Cancer by Repressing GPNMB via Positively Regulating Transcription Factor MITF","volume":"235","author":"Li","year":"2020","journal-title":"J Cell Physiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-16-0285","article-title":"Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1","volume":"15","author":"Ikezono","year":"2017","journal-title":"Mol Cancer Res"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELREP.2014.05.010","article-title":"RNA Helicases DDX5 and DDX17 Dynamically Orchestrate Transcription, miRNA, and Splicing Programs in Cell Differentiation","volume":"7","author":"Dardenne","year":"2014","journal-title":"Cell Rep"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.7150\/JCA.19594","article-title":"Eukaryotic Translation Initiation Factor 3b Is Both a Promising Prognostic Biomarker and a Potential Therapeutic Target for Patients With Clear Cell Renal Cell Carcinoma","volume":"8","author":"Zang","year":"2017","journal-title":"J Cancer"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/J.YEXCR.2019.111806","article-title":"GRWD1 Promotes Cell Proliferation and Migration in Non-Small Cell Lung Cancer by Activating the Notch Pathway","volume":"387","author":"Wang","year":"2020","journal-title":"Exp Cell Res"},{"key":"B55","article-title":"b-Asarone Inhibits Invasion and EMT in Human Glioma U251 Cells by Suppressing Splicing Factor HnRNP A2\/B1","volume":"23","author":"Li","year":"2018","journal-title":"Molecules"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/ONC.2011.199","article-title":"EPLIN Downregulation Promotes Epithelial-Mesenchymal Transition in Prostate Cancer Cells and Correlates With Clinical Lymph Node Metastasis","volume":"30","author":"Zhang","year":"2011","journal-title":"Oncogene"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/J.CANLET.2015.05.023","article-title":"Silencing of LRRFIP1 Reverses the Epithelial-Mesenchymal Transition via Inhibition of the Wnt\/b-Catenin Signaling Pathway","volume":"365","author":"Douchi","year":"2015","journal-title":"Cancer Lett"},{"key":"B58","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1186\/S12885-019-6119-X","article-title":"Interaction of hnRNP K With MAP 1B-LC1 Promotes TGF-b1-Mediated Epithelial to Mesenchymal Transition in Lung Cancer Cells","volume":"19","author":"Li","year":"2019","journal-title":"BMC Cancer"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-12-0511","article-title":"Stem Cell Marker Nestin Is Critical for TGF-b1-Mediated Tumor Progression in Pancreatic Cancer","volume":"11","author":"Su","year":"2013","journal-title":"Mol Cancer Res"},{"key":"B60","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1038\/s41419-018-1030-y","article-title":"Keratin 80 Promotes Migration and Invasion of Colorectal Carcinoma by Interacting With PRKDC via Activating the AKT Pathway","volume":"9","author":"Li","year":"2018","journal-title":"Cell Death Dis"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1007\/S10549-013-2809-2","article-title":"Sorcin Silencing Inhibits Epithelial-to-Mesenchymal Transition and Suppresses Breast Cancer Metastasis In Vivo","volume":"143","author":"Hu","year":"2014","journal-title":"Breast Cancer Res Treat"},{"key":"B62","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/nrd.2016.193","article-title":"Tumour-Associated Mesenchymal Stem\/Stromal Cells: Emerging Therapeutic Targets","volume":"16","author":"Shi","year":"2016","journal-title":"Nat Rev Drug Discov"},{"key":"B63","doi-asserted-by":"publisher","first-page":"67","DOI":"10.4252\/wjsc.v2.i4.67","article-title":"Mesenchymal Stem Cells: Molecular Characteristics and Clinical Applications","volume":"2","author":"Rastegar","year":"2010","journal-title":"World J Stem Cells"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2015.01.010","article-title":"Q2 Hypoxia Enhances Migration and Invasion in Glioblastoma by Promoting a Mesenchymal Shift Mediated by the HIF1a-ZEB1 Axis","volume":"359","author":"Joseph","year":"2015","journal-title":"Cancer Lett"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208649","article-title":"Identification of Novel VHL Target Genes and Relationship to Hypoxic Response Pathways","volume":"24","author":"Maina","year":"2005","journal-title":"Oncogene"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511408200","article-title":"Concordant Regulation of Gene Expression by Hypoxia and 2-Oxoglutarate-Dependent Dioxygenase Inhibition THE ROLE OF HIF-1, HIF-2, AND OTHER PATHWAYS * \u25a1 S","volume":"281","author":"Elvidge","year":"2006","journal-title":"J Biol Chem"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-0388","article-title":"Tumor and Stem Cell Biology Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C\/EBPb Signaling","volume":"77","author":"Yin","year":"2017","journal-title":"Cancer Res"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0049321","article-title":"Tissue Transglutaminase Constitutively Activates HIF-1a Promoter and Nuclear Factor-kB via a Non-Canonical Pathway","volume":"7","author":"Kumar","year":"2012","journal-title":"PloS One"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.2217\/fon.12.27","article-title":"GPR56 in Cancer Progression: Current Status and Future Perspective","volume":"8","author":"Yang","year":"2012","journal-title":"Futur Oncol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1593\/neo.121878","article-title":"Extracellular Tissue Transglutaminase Activates Noncanonical NF-kb Signaling and Promotes Metastasis in Ovarian Cancer","volume":"15","author":"Yakubov","year":"2013","journal-title":"Neoplasia (United States)"},{"key":"B71","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1152\/physrev.00019.2013","article-title":"Transglutaminase Regulation of Cell Function","volume":"94","author":"Eckert","year":"2014","journal-title":"Physiol Rev"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/J.BBRC.2012.04.082","article-title":"Detection of Transglutaminase 2 Conformational Changes in Living Cell","volume":"421","author":"Pavlukov","year":"2012","journal-title":"Biochem Biophys Res Commun"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1016\/J.BBAMCR.2016.01.018","article-title":"Calcium Signaling Orchestrates Glioblastoma Development: Facts and Conjunctures","volume":"1863","author":"Leclerc","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013390","article-title":"Tissue Transglutaminase Promotes Drug Resistance and Invasion by Inducing Mesenchymal Transition in Mammary Epithelial Cells","volume":"5","author":"Kumar","year":"2010","journal-title":"PloS One"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.342","article-title":"Transglutaminase 2 Suppresses Apoptosis by Modulating Caspase 3 and NF-kB Activity in Hypoxic Tumor Cells","volume":"29","author":"Jang","year":"2010","journal-title":"Oncogene"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1007\/S11060-010-0277-7","article-title":"The Transglutaminase 2 Gene Is Aberrantly Hypermethylated in Glioma","volume":"101","author":"Dyer","year":"2011","journal-title":"J Neurooncol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9699","article-title":"Long Noncoding RNA RP11-838N2.4 Enhances the Cytotoxic Effects of Temozolomide by Inhibiting the Functions of miR-10a in Glioblastoma Cell Lines","volume":"7","author":"Liu","year":"2016","journal-title":"Oncotarget"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.841890\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T19:39:26Z","timestamp":1651779566000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.841890\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,3]]},"references-count":77,"alternative-id":["10.3389\/fonc.2022.841890"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.841890","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,3]]},"article-number":"841890"}}