Empty spiracles homeobox genes EMX1 and EMX2 regulate WNT pathway activation in sarcomagenesis
説明
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>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.<jats:italic>EMX</jats:italic>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<jats:italic>EMX1</jats:italic>or<jats:italic>EMX2</jats:italic>overexpression reduces tumorigenic properties, while reducing the levels of these genes enhances these properties. Furthermore, it has been shown that<jats:italic>EMX</jats:italic>genes decrease the expression of stem cell regulatory genes and the stem cell phenotype. Taken together, these results indicate that the<jats:italic>EMX1</jats:italic>and<jats:italic>EMX2</jats:italic>genes negatively regulate these tumor-remodeling populations or sarcoma stem cells, acting as tumor suppressors in sarcoma.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In this work, we showed that the canonical Wnt pathway is one of the mechanisms that explains the relationships of<jats:italic>EMX1</jats:italic>/<jats:italic>EMX2</jats:italic>and stem cell genes in sarcoma. The Wnt-<jats:italic>EMX1</jats:italic>/<jats:italic>EMX2</jats:italic>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<jats:italic>EMX1</jats:italic>and/or<jats:italic>EMX2</jats:italic>overexpression, establishing the relationship among the Wnt pathway, stem cell genes and the<jats:italic>EMX</jats:italic>transcription factors.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>
収録刊行物
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- Journal of Experimental & Clinical Cancer Research
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Journal of Experimental & Clinical Cancer Research 40 2021-08-07
Springer Science and Business Media LLC
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キーワード
- Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology
- Carcinogenesis
- Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors
- Wnt pathway
- Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic
- Medical Subject Headings::Diseases::Neoplasms
- Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Gene Transfer Techniques::Transfection
- b-catenin
- Transfection
- Empty Spiracles Homeobox
- Transgenic Mice
- Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
- Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line
- Cancer Stem Cells
- Medical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Connective and Soft Tissue::Sarcoma
- Humans
- Stemness
- Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Developmental::Genes, Homeobox
- Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Regulator
- Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Cytoskeletal Proteins::Catenins
- Wnt Signaling Pathway
- Sarcomagenesis
- RC254-282
- Cancer
- Homeodomain Proteins
- EMX
- Cancer stem cells
- Neoplasms. Tumors. Oncology. Including cancer and carcinogens
- Medical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::Carcinogenesis
- Sarcoma
- WNT Pathway
- Medical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger
- Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Chemical Processes::Biochemical Processes::Signal Transduction::Wnt Signaling Pathway
- Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::DNA-Binding Proteins::Homeodomain Proteins
- Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype
- Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression::Transcription, Genetic
- EMX1
- EMX2
- b‑catenin
- Medical Subject Headings::Anatomy::Cells::Stem Cells::Neoplastic Stem Cells
- Transcription Factors
詳細情報 詳細情報について
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- CRID
- 1871991018156710912
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- ISSN
- 17569966
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- HANDLE
- 10261/266242
- 10668/4507
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- PubMed
- 34364391
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- データソース種別
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- OpenAIRE