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dc.contributor.authorFranke, F. C.
dc.contributor.authorMüller, J.
dc.contributor.authorAbal Posada, Miguel 
dc.contributor.authorMedina, E. D.
dc.contributor.authorNitsche, U.
dc.contributor.authorWeidmann, H.
dc.contributor.authorChardonnet, S.
dc.contributor.authorNinio, E.
dc.contributor.authorJanssen, K. P.
dc.date.accessioned2021-11-30T11:11:14Z
dc.date.available2021-11-30T11:11:14Z
dc.date.issued2019
dc.identifier.issn2352-345X
dc.identifier.otherhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251370/pdf/main.pdfes
dc.identifier.otherhttps://www.ncbi.nlm.nih.gov/pubmed/30480076es
dc.identifier.urihttp://hdl.handle.net/20.500.11940/15765
dc.description.abstractBackground & Aims: The tumor-suppressor sterile alpha motif- and Src-homology 3-domain containing 1 (SASH1) has clinical relevance in colorectal carcinoma and is associated specifically with metachronous metastasis. We sought to identify the molecular mechanisms linking decreased SASH1 expression with distant metastasis formation. Methods: SASH1-deficient, SASH1-depleted, or SASH1-overexpressing HCT116 colon cancer cells were generated by the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9-method, RNA interference, and transient plasmid transfection, respectively. Epithelial-mesenchymal transition (EMT) was analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblotting, immunofluorescence microscopy, migration/invasion assays, and 3-dimensional cell culture. Yeast 2-hybrid assays and co-immunoprecipitation/mass-spectrometry showed V-Crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) as a novel interaction partner of SASH1, further confirmed by domain mapping, site-directed mutagenesis, co-immunoprecipitation, and dynamic mass redistribution assays. CRKL-deficient cells were generated in parental or SASH1-deficient cells. Metastatic capacity was analyzed with an orthotopic mouse model. Expression and significance of SASH1 and CRKL for survival and response to chemotherapy was assessed in patient samples from our department and The Cancer Genome Atlas data set. Results: SASH1 expression is down-regulated during cytokine-induced EMT in cell lines from colorectal, pancreatic, or hepatocellular cancer, mediated by the putative SASH1 promoter. Deficiency or knock-down of SASH1 induces EMT, leading to an aggressive, invasive phenotype with increased chemoresistance. SASH1 counteracts EMT through interaction with the oncoprotein CRKL, inhibiting CRKL-mediated activation of SRC kinase, which is crucially required for EMT. SASH1-deficient cells form significantly more metastases in vivo, depending entirely on CRKL. Patient tumor samples show significantly decreased SASH1 and increased CRKL expression, associated with significantly decreased overall survival. Patients with increased CRKL expression show significantly worse response to adjuvant chemotherapy. Conclusions: We propose SASH1 as an inhibitor of CRKL-mediated SRC signaling, introducing a potentially druggable mechanism counteracting chemoresistance and metastasis formation.en
dc.language.isoenges
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subject.meshCRISPR-Cas Systems*
dc.subject.meshTumor Suppressor Proteins*
dc.subject.meshsrc Homology Domains*
dc.subject.meshNeoplasm Invasiveness*
dc.subject.meshNeoplasm Metastasis*
dc.subject.meshHCT116 Cells*
dc.subject.meshPhenotype*
dc.subject.meshSignal Transduction*
dc.subject.meshEpithelial-Mesenchymal Transition*
dc.subject.meshProtein Binding*
dc.subject.meshNuclear Proteins*
dc.subject.meshHEK293 Cells*
dc.subject.meshHumans*
dc.subject.meshAmino Acid Motifs*
dc.subject.meshColorectal Neoplasms*
dc.titleThe Tumor Suppressor SASH1 Interacts With the Signal Adaptor CRKL to Inhibit Epithelial–Mesenchymal Transition and Metastasis in Colorectal Canceren
dc.typeArtigoes
dc.authorsophosFranke, F. C.
dc.authorsophosMüller, J.
dc.authorsophosAbal, M.
dc.authorsophosMedina, E. D.
dc.authorsophosNitsche, U.
dc.authorsophosWeidmann, H.
dc.authorsophosChardonnet, S.
dc.authorsophosNinio, E.
dc.authorsophosJanssen, K. P.
dc.identifier.doi10.1016/j.jcmgh.2018.08.007
dc.identifier.pmid30480076
dc.identifier.sophos31741
dc.issue.number1es
dc.journal.titleCELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGYes
dc.organizationServizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS)es
dc.page.initial33es
dc.page.final53es
dc.rights.accessRightsopenAccesses
dc.subject.decsproteínas nucleares*
dc.subject.decsfenotipo*
dc.subject.decsdominios de homología src*
dc.subject.decsunión proteica*
dc.subject.decssistemas CRISPR-Cas*
dc.subject.decsmetástasis neoplásica*
dc.subject.decsmotivos de aminoácidos*
dc.subject.decstransducción de señales*
dc.subject.decscélulas HCT116*
dc.subject.decsproteínas supresoras de tumor*
dc.subject.decsinvasividad neoplásica*
dc.subject.decstransición epiteliomesenquimatosa*
dc.subject.decshumanos*
dc.subject.decsneoplasias colorrectales*
dc.subject.decscélulas HEK293*
dc.subject.keywordIDISes
dc.typefidesArtículo Originales
dc.typesophosArtículo Originales
dc.volume.number7es


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Attribution-NonCommercial-NoDerivatives 4.0 International
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