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The purpose of this study was to clarify the clinical value of biglycan as a biomarker in multiple independent GC cohorts and determine the in vitro and in vivo role of biglycan in GC malignant features. We found that BGN is commonly over-expressed in all analyzed cohorts, being associated with disease relapse and poor prognosis in patients with advanced stages of disease. In vitro and in vivo experiments demonstrated that biglycan knock-out GC cells display major phenotypic changes with a lower cell survival, migration, and angiogenic potential when compared with biglycan expressing cells. Biglycan KO GC cells present increased levels of PARP1 and caspase-3 cleavage and a decreased expression of mesenchymal markers. Importantly, biglycan deficient GC cells that were supplemented with exogenous biglycan were able to restore biological features, such as survival, clonogenic and migratory capacities. Our in vitro and in vivo findings were validated in human GC samples, where BGN expression was associated with several oncogenic gene signatures that were associated with apoptosis, cell migration, invasion, and angiogenesis. This study provided new insights on biglycan role in GC that should be taken in consideration as a key cellular regulator with major impact in tumor progression and patients\u2019 clinical outcome.<\/jats:p>","DOI":"10.3390\/cancers13061330","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T12:01:02Z","timestamp":1615896062000},"page":"1330","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["The Extracellular Small Leucine-Rich Proteoglycan Biglycan Is a Key Player in Gastric Cancer Aggressiveness"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2330-9863","authenticated-orcid":false,"given":"Filipe","family":"Pinto","sequence":"first","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1937-1904","authenticated-orcid":false,"given":"Liliana","family":"Santos-Ferreira","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, 4200-135 Porto, Portugal"},{"name":"Faculty of Sciences of the University of Porto (FCUP), University of Porto, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8521-2904","authenticated-orcid":false,"given":"Marta","family":"Pinto","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0352-6783","authenticated-orcid":false,"given":"Catarina","family":"Gomes","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0286-6639","authenticated-orcid":false,"given":"Celso","family":"Reis","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, 4200-135 Porto, Portugal"},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"},{"name":"Faculty of Medicine of the University of Porto (FMUP), University of Porto, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. 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