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1. Dynamic regulation of O-GlcNAcylation and phosphorylation on STAT3 under hypoxia-induced EMT.

Author

Fu Y, Ning L, Feng J, Yu X, Guan F, and Li X

Subjects
Humans, Hypoxia, Phosphorylation, Ubiquitination, Epithelial-Mesenchymal Transition genetics, STAT3 Transcription Factor metabolism
Abstract

Activation of signal transducer and activator of transcription 3 (STAT3) is associated with hypoxia-induced epithelial-mesenchymal transition (EMT). Activation of STAT3 requires its phosphorylated form, and STAT3 can also be post-translationally modified by O-GlcNAcylation. Dynamic regulation of STAT3 O-GlcNAcylation in relation to STAT3 phosphorylation remains poorly understood. We observed, based on chemical enzyme labeling and click chemistry methods in combination with mass spectrometric analysis, that O-GlcNAcylation of STAT3 is significantly reduced under hypoxia. Results of functional experiments indicated that O-GlcNAcylation maintains stability of STAT3 and prevents its degradation via ubiquitination during hypoxia-induced EMT. O-GlcNAcylation of STAT3 facilitated its phosphorylation. Following STAT3 phosphorylation, existing STAT3 O-GlcNAcylation was antagonistically released. Our experimental findings, in combination with structure modeling, indicate that O-GlcNAcylation of STAT3 at residue T717 is essential for its phosphorylation at Y705. In contrast, mutation of STAT3 at phosphorylation site Y705 had no effect on its O-GlcNAcylation. O-GlcNAcylation and phosphorylation of STAT3 evidently occur in a strict sequential order under hypoxia-induced EMT. Dynamic regulation of STAT3 function clearly involves crosstalk between O-GlcNAcylation and phosphorylation. O-GlcNAcylation of STAT3 at T717 facilitates EMT process by promoting STAT3 phosphorylation, and provides a potential therapeutic target that may be useful in anticancer drug design., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2022
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2. Circulating Tumor Cells: A Review of Non-EpCAM-Based Approaches for Cell Enrichment and Isolation

Author

Antoine Chalopin, Benjamin Ory, Lidia Rodriguez Calleja, Marta Tellez Gabriel, Dominique Heymann, Equipe LIGUE Nationale Contre le Cancer 2012, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], This paper was written as a part of research project which received funding from the Seventh Framework Program [(FP7/2007-2013) under grant agreement no. 264817—BONE-NET and this work was supported by the Fondation de France (Engt no. 16390)]., European Project: 264817,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,BONE-NET(2011), Heymann, Dominique, and European Training Network on Cancer-Induced Bone Diseases - BONE-NET - - EC:FP7:PEOPLE2011-02-01 - 2015-01-31 - 264817 - VALID

Subjects
0301 basic medicine, Epithelial-Mesenchymal Transition, Clinical Biochemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Separation, Biology, Cell enrichment, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Circulating tumor cell, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Antigen, Single-cell analysis, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, Biomarkers, Tumor, Humans, Epithelial–mesenchymal transition, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Biochemistry (medical), Mesenchymal stem cell, Epithelial cell adhesion molecule, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Epithelial Cell Adhesion Molecule, Neoplastic Cells, Circulating, 3. Good health, 030104 developmental biology, chemistry, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, Immunology, Cancer research, Personalized medicine, Single-Cell Analysis, business, Cell Adhesion Molecules
Abstract

BACKGROUND Circulating tumor cells (CTCs) are biomarkers for noninvasively measuring the evolution of tumor genotypes during treatment and disease progression. Recent technical progress has made it possible to detect and characterize CTCs at the single-cell level in blood. CONTENT Most current methods are based on epithelial cell adhesion molecule (EpCAM) detection, but numerous studies have demonstrated that EpCAM is not a universal marker for CTC detection because it fails to detect both carcinoma cells that undergo epithelial-mesenchymal transition (EMT) and CTCs of mesenchymal origin. Moreover, EpCAM expression has been found in patients with benign diseases. A large proportion of the current studies and reviews about CTCs describe EpCAM-based methods, but there is evidence that not all tumor cells can be detected using this marker. Here we describe the most recent EpCAM-independent methods for enriching, isolating, and characterizing CTCs on the basis of physical and biological characteristics and point out the main advantages and disadvantages of these methods. SUMMARY CTCs offer an opportunity to obtain key biological information required for the development of personalized medicine. However, there is no universal marker of these cells. To strengthen the clinical utility of CTCs, it is important to improve existing technologies and develop new, non–EpCAM-based systems to enrich and isolate CTCs.

Published
2016

3. p53 regulates epithelial–mesenchymal transition through microRNAs targeting ZEB1 and ZEB2

Author

Young-Jun Jeon, Flavia Pichiorri, Angelo Veronese, Pascal Pineau, Anne Dejean, Tae Jin Lee, Hansjuerg Alder, Agnès Marchio, Stefano Volinia, Taewan Kim, Jeff Palatini, Chang Gong Liu, Sung Suk Suh, Carlo M. Croce, Comprehensive Cancer Center [Colombus], Ohio State University [Columbus] (OSU), Molecular, Cellular, and Developmental Biology Program [Columbus] (MCDB), Organisation Nucléaire et Oncogenèse, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was funded by National Cancer Institute grant RC2 CA148302., We thank Dr. B. Vogelstein for p53+/+ and p53−/− RKO cells, Dr. Gustavo Leone for p53+/+ and p53−/− MEFs, Dr. Gregory J. Goodall for pCIneo-hRL-ZEB1/2 constructs, and Dr. Anders H. Lund for pcDNA3-Zeb2-HA constructs. We also thank Dr. Kay Huebner (The Ohio State University), Dr. Thomas D. Schmittgen (The Ohio State University), and Susan Lutz for careful editing of this paper, and Sharon Palko and Dorothee Wernicke-Jameson for the administrative support., Pineau, Pascal, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, MESH: Zinc Finger E-box-Binding Homeobox 1, genetics/metabolism, biosynthesis/genetics, Metastasis, genetics/metabolism/pathology, 0302 clinical medicine, MESH: Liver Neoplasms, Immunology and Allergy, genetics, RNA, Neoplasm, Neoplasm Metastasis, MESH: Carcinoma, Hepatocellular, MESH: Tumor Suppressor Protein p53, 0303 health sciences, digestive, oral, and skin physiology, Liver Neoplasms, Hep G2 Cells, MESH: Gene Expression Regulation, Neoplastic, MESH: Transcription Factors, Gene Expression Regulation, Neoplastic, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, embryonic structures, Female, Transcriptional Activation, Carcinoma, Hepatocellular, Epithelial-Mesenchymal Transition, Immunology, Repressor, MESH: Hep G2 Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, MESH: Gene Expression Profiling, [SDV.CAN] Life Sciences [q-bio]/Cancer, microRNA, MESH: Homeodomain Proteins, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epithelial–mesenchymal transition, Transcription factor, Zinc Finger E-box Binding Homeobox 2, 030304 developmental biology, MESH: Zinc Finger E-box Binding Homeobox 2, Homeodomain Proteins, Neoplastic, MESH: Humans, Gene Expression Profiling, Carcinoma, Brief Definitive Report, Zinc Finger E-box-Binding Homeobox 1, Hepatocellular, Cell Biology, HCCS, medicine.disease, MESH: RNA, Neoplasm, MESH: Neoplasm Metastasis, MESH: Male, Repressor Proteins, Gene expression profiling, MicroRNAs, MESH: Epithelial-Mesenchymal Transition, Gene Expression Regulation, Tumor progression, Cancer research, RNA, Neoplasm, MESH: Transcriptional Activation, genetics/metabolism/pathology, Epithelial-Mesenchymal Transition, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Hep G2 Cells, Homeodomain Proteins, biosynthesis/genetics, Humans, Liver Neoplasms, genetics/metabolism/pathology, Male, MicroRNAs, genetics/metabolism, Neoplasm Metastasis, RNA, genetics/metabolism, Repressor Proteins, biosynthesis/genetics, Transcription Factors, biosynthesis/genetics, Transcriptional Activation, genetics, Tumor Suppressor Protein p53, Tumor Suppressor Protein p53, MESH: Female, MESH: MicroRNAs, 030215 immunology, Transcription Factors
Abstract

By transactivating expression of miRNAs that repress expression of the ZEB1 and ZEB2 transcription factors, p53 inhibits the epithelial–mesenchymal transition., p53 suppresses tumor progression and metastasis. Epithelial–mesenchymal transition (EMT) is a key process in tumor progression and metastasis. The transcription factors ZEB1 and ZEB2 promote EMT. Here, we show that p53 suppresses EMT by repressing expression of ZEB1 and ZEB2. By profiling 92 primary hepatocellular carcinomas (HCCs) and 9 HCC cell lines, we found that p53 up-regulates microRNAs (miRNAs), including miR-200 and miR-192 family members. The miR-200 family members transactivated by p53 then repress ZEB1/2 expression. p53-regulated miR-192 family members also repress ZEB2 expression. Inhibition or overexpression of the miRNAs affects p53-regulated EMT by altering ZEB1 and ZEB2 expression. Our findings indicate that p53 can regulate EMT, and that p53-regulated miRNAs are critical mediators of p53-regulated EMT.

Published
2011