Empty spiracles homeobox genes EMX1 and EMX2 regulate WNT pathway activation in sarcomagenesis

Autor: Daniel Otero-Albiol, Antonio Lucena-Cacace, Manuel P. Jiménez-García, Amancio Carnero
Přispěvatelé: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Centro de Investigación Biomédica en Red Cáncer (España), Junta de Andalucía, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Educación, Cultura y Deporte (España), [Jimenez-García,MP, Otero-Albiol,D, Carnero,A] Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Sevilla, Spain. [Jimenez-García,MP, Carnero,A] CIBER de Cancer, IS Carlos III, Madrid, Spain. [Lucena-Cacace,A] Present address: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan. [Carnero,A] Instituto de Biomedicina de Sevilla/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Sevilla, Spain., This work was supported by grants from the Ministerio de Ciencia, Innovación y Universidades (MCIU) Plan Estatal de I + D + I 2018, a la Agencia Estatal de Investigación (AEI) y al Fondo Europeo de Desarrollo Regional (MCIU/AEI/FEDER, UE): RTI2018-097455-B-I00, from AEI-MICIU/FEDER (RED2018-102723-T), from CIBER de Cáncer (CB16/12/00275), co-funded by FEDER from Regional Development European Funds (European Union), from Consejeria de Salud (PI-0397–2017) and Consejeria of Economía, Conocimiento, Empresas y Universidad of the Junta de Andalucia (P18-RT-2501). Also especial thanks to the Fundacion AECC for supporting this work. MPJ-G was funded by a FPU contract from the Ministerio de Educacion (FPU13/00426).
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Cancer Research
Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings]
beta Catenina
Carcinogenesis
EMX1
Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms
Connective and Soft Tissue::Sarcoma [Medical Subject Headings]
Anatomy::Cells::Stem Cells::Neoplastic Stem Cells [Medical Subject Headings]
medicine.disease_cause
b-catenin
Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings]
Anatomy::Cells::Cells
Cultured::Cell Line [Medical Subject Headings]
Wnt Signaling Pathway
RC254-282
Cancer
Phenomena and Processes::Chemical Phenomena::Chemical Processes::Biochemical Processes::Signal Transduction::Wnt Signaling Pathway [Medical Subject Headings]
EMX
Chemicals and Drugs::Amino Acids
Peptides
and Proteins::Proteins::DNA-Binding Proteins::Homeodomain Proteins [Medical Subject Headings]
Cancer stem cells
Línea celular
Wnt signaling pathway
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Sarcoma
Diseases::Neoplasms::Neoplastic Processes::Carcinogenesis [Medical Subject Headings]
Diseases::Neoplasms [Medical Subject Headings]
Neoplasias
Cell biology
ARN
Phenotype
Oncology
Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology [Medical Subject Headings]
Cell lines
Stem cell
Fenotipo
Regulatory genes
Vía de señalización Wnt
Wnt pathway
Biology
Transfection
Chemicals and Drugs::Amino Acids
Peptides
and Proteins::Proteins::Transcription Factors [Medical Subject Headings]
Factores de transcripción
Cancer stem cell
medicine
Humans
Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression::Transcription
Genetic [Medical Subject Headings]
Células madre neoplásicas
Homeodomain Proteins
Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes
Regulator [Medical Subject Headings]
Genes reguladores
Research
fungi
Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis
Genetic [Medical Subject Headings]
Chemicals and Drugs::Nucleic Acids
Nucleotides
and Nucleosides::Nucleic Acids::RNA::RNA
Messenger [Medical Subject Headings]
Chemicals and Drugs::Amino Acids
Peptides
and Proteins::Proteins::Cytoskeletal Proteins::Catenins [Medical Subject Headings]
Catenin
Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes
Developmental::Genes
Homeobox [Medical Subject Headings]
Homeobox
RNA
Ectopic expression
b‑catenin
Analytical
Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Gene Transfer Techniques::Transfection [Medical Subject Headings]
Transcription Factors
Zdroj: Journal of Experimental & Clinical Cancer Research : CR
Digital.CSIC. Repositorio Institucional del CSIC
instname
Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-18 (2021)
ISSN: 1756-9966
0392-9078
Popis: [Background] Sarcomas are a very heterogeneous group of tumors with intrinsic developmental programs derived from the cell of origin. This implies a functional hierarchy inside tumors governed by sarcoma stem cells. Therefore, genetic and/or epigenetic changes profoundly affect the biology of sarcoma tumor stem cells. EMX genes are proposed to be transcription factors that are involved in the sarcomagenesis process, regardless of the neural or mesodermal embryological sarcoma origin. It has been shown that EMX1 or EMX2 overexpression reduces tumorigenic properties, while reducing the levels of these genes enhances these properties. Furthermore, it has been shown that EMX genes decrease the expression of stem cell regulatory genes and the stem cell phenotype. Taken together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-remodeling populations or sarcoma stem cells, acting as tumor suppressors in sarcoma.
[Methods] Bioinformatic analysis, quantitative mRNA and protein expression analysis, cell models of sarcoma by ectopic expression of EMX genes. By cell biology methods we measured tumorigenesis and populations enriched on stem cell phenotypes, either in vitro or in vivo.
[Results] In this work, we showed that the canonical Wnt pathway is one of the mechanisms that explains the relationships of EMX1/EMX2 and stem cell genes in sarcoma. The Wnt-EMX1/EMX2 relationship was validated in silico with sarcoma patient datasets, in vitro in primary derived sarcoma cell lines, and in vivo. EMX expression was found to negatively regulate the Wnt pathway. In addition, the constitutive activation of the Wnt pathway revers to a more aggressive phenotype with stem cell properties, and stemness gene transcription increased even in the presence of EMX1 and/or EMX2 overexpression, establishing the relationship among the Wnt pathway, stem cell genes and the EMX transcription factors.
[Conclusions] Our data showed that Empty Spiracles Homeobox Genes EMX1 and EMX2 represses WNT signalling and activation of WNT pathway bypass EMX-dependent stemness repression and induces sarcomagenesis. These results also suggest the relevance of the Wnt/b-catenin/stemness axis as a therapeutic target in sarcoma.
This work was supported by grants from the Ministerio de Ciencia, Innovación y Universidades (MCIU) Plan Estatal de I + D + I 2018, a la Agencia Estatal de Investigación (AEI) y al Fondo Europeo de Desarrollo Regional (MCIU/AEI/FEDER, UE): RTI2018-097455-B-I00; from AEI-MICIU/FEDER (RED2018-102723-T); from CIBER de Cáncer (CB16/12/00275), co-funded by FEDER from Regional Development European Funds (European Union); from Consejeria de Salud (PI-0397–2017) and Consejeria of Economía, Conocimiento, Empresas y Universidad of the Junta de Andalucia (P18-RT-2501). Also especial thanks to the Fundacion AECC for supporting this work. MPJ-G was funded by a FPU contract from the Ministerio de Educacion (FPU13/00426).
Databáze: OpenAIRE
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