title: Dies1/VISTA expression loss is a recurrent event in gastric cancer due to epigenetic regulation.
abstract: Dies1/VISTA induces embryonic stem-cell differentiation, via BMP-pathway, but also acts as inflammation regulator and immune-response modulator. Dies1 inhibition in a melanoma-mouse model led to increased tumour-infiltrating T-cells and decreased tumour growth, emphasizing Dies1 relevance in tumour-microenvironment. Dies1 is involved in cell de/differentiation, inflammation and cancer processes, which mimic those associated with Epithelial-to-Mesenchymal-Transition (EMT). Despite this axis linking Dies1 with EMT and cancer, its expression, modulation and relevance in these contexts is unknown. To address this, we analysed Dies1 expression, its regulation by promoter-methylation and miR-125a-5p overexpression, and its association with BMP-pathway downstream-effectors, in a TGFβ1-induced EMT-model, cancer cell-lines and primary samples. We detected promoter-methylation as a mechanism controlling Dies1 expression in our EMT-model and in several cancer cell-lines. We showed that the relationship between Dies1 expression and BMP-pathway effectors observed in the EMT-model, was not present in all cell-lines, suggesting that Dies1 has other cell-specific effectors, beyond the BMP-pathway. We further demonstrated that: Dies1 expression loss is a recurrent event in GC, caused by promoter methylation and/or miR-125a-5p overexpression and; GC-microenvironment myofibroblasts overexpress Dies1. Our findings highlight Dies1 as a novel player in GC, with distinct roles within tumour cells and in the tumour-microenvironment.
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.|IPATIMUP- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-465 Porto, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Oliveira
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.|IPATIMUP- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-465 Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Carvalho
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.|IPATIMUP- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-465 Porto, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Rocha
authors.affiliation: IPATIMUP- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-465 Porto, Portugal.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Azevedo
authors.affiliation: IPATIMUP- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-465 Porto, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Reis
authors.affiliation: IPATIMUP- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-465 Porto, Portugal.
authors.forename: Vânia
authors.initials: V
authors.lastname: Camilo
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.|IPATIMUP- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-465 Porto, Portugal.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Sousa
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.|IPATIMUP- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-465 Porto, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Valente
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.|IPATIMUP- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-465 Porto, Portugal.|Dept. Pathology and Oncology, Faculty of Medicine, University of Porto, 4200-465 Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Paredes
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.|IPATIMUP- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-465 Porto, Portugal.|Dept. Pathology and Oncology, Faculty of Medicine, University of Porto, 4200-465 Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Almeida
authors.affiliation: British Columbia Cancer Agency (BCCA), Vancouver V5Z 4E6, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.|IPATIMUP- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-465 Porto, Portugal.|Dept. Pathology and Oncology, Faculty of Medicine, University of Porto, 4200-465 Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
mesh_terms: D060887:B7 Antigens / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D060887:B7 Antigens; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D053773:Transforming Growth Factor beta1; C000588758:VSIR protein, human; C075640:ID3 protein, human