Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease
Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In...
| Autores: | , , , , , , , , , , , , , |
|---|---|
| Tipo de documento: | artigo |
| Data de publicação: | 2016 |
| País: | España |
| Recursos: | Universidad de Navarra |
| Repositório: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglês |
| OAI Identifier: | oai:dadun.unav.edu:10171/56666 |
| Acesso em linha: | https://hdl.handle.net/10171/56666 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Hepatocarcinogenesis Stem cells Progression Gene expression profile Yap targets |
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Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human diseaseSimile, M.M. (María M.)|||/items/01afd25c-f5fa-4ff3-92db-75dce6789ad8Latte, G. (Gavinella)|||/items/1cd0beea-30dd-48ee-a6aa-03feaac05bf1Demartis, M.I. (María I.)|||/items/a1d5abf8-3d62-4f96-85f5-79b53728c2deBrozzetti, S. (Stefania)|||/items/56a0b227-78fc-4fa4-a7aa-901439ce28c6Calvisi, D.F. (Diego F.)|||/items/f1fd12a7-edff-43c9-a8a8-425bd3a0d865Porcu, A. (Alberto)|||/items/a66c4daf-5f11-457a-9ba0-bde71133d46cFeo, C.F. (Claudio F.)|||/items/7d78d8fc-c7c2-43c3-9549-7c9fcbbf6becSeddaiu, M.A. (María A.)|||/items/172dfdd3-a500-4368-8c7c-cd00532ebc19Daino, L. (Lucia)|||/items/6d5efc12-1684-4fbf-a119-8ee6e3611da7Berasain-Lasarte, C. (Carmen)|||/items/f1d61c19-1753-4442-a3fd-cc90220e84a0Tomasi, M.L. (María L.)|||/items/ddfc4380-6698-4ccc-8642-72593b1b15e1Avila, M.A. (Matías Antonio)|||/items/3ad9abbb-c18d-445b-86cf-cb76be15419fFeo, F. (Francesco)|||/items/99bd4be9-e6a1-43aa-8070-fe350bf4d9a7Pascale, R.M. (Rosa M.)|||/items/8bc06856-fd21-4dd5-80c4-c8fff8aac3adHepatocarcinogenesisStem cellsProgressionGene expression profileYap targetsPrevious studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1- tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of YAP1, CTGF, 14–3–3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells.Impact JournalsDadun. Depósito Académico Digital Universidad de Navarra20192019-04-0120162016-01-2320162016-01-23journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/56666reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/566662026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease |
| title |
Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease |
| spellingShingle |
Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease Simile, M.M. (María M.)|||/items/01afd25c-f5fa-4ff3-92db-75dce6789ad8 Hepatocarcinogenesis Stem cells Progression Gene expression profile Yap targets |
| title_short |
Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease |
| title_full |
Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease |
| title_fullStr |
Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease |
| title_full_unstemmed |
Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease |
| title_sort |
Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease |
| dc.creator.none.fl_str_mv |
Simile, M.M. (María M.)|||/items/01afd25c-f5fa-4ff3-92db-75dce6789ad8 Latte, G. (Gavinella)|||/items/1cd0beea-30dd-48ee-a6aa-03feaac05bf1 Demartis, M.I. (María I.)|||/items/a1d5abf8-3d62-4f96-85f5-79b53728c2de Brozzetti, S. (Stefania)|||/items/56a0b227-78fc-4fa4-a7aa-901439ce28c6 Calvisi, D.F. (Diego F.)|||/items/f1fd12a7-edff-43c9-a8a8-425bd3a0d865 Porcu, A. (Alberto)|||/items/a66c4daf-5f11-457a-9ba0-bde71133d46c Feo, C.F. (Claudio F.)|||/items/7d78d8fc-c7c2-43c3-9549-7c9fcbbf6bec Seddaiu, M.A. (María A.)|||/items/172dfdd3-a500-4368-8c7c-cd00532ebc19 Daino, L. (Lucia)|||/items/6d5efc12-1684-4fbf-a119-8ee6e3611da7 Berasain-Lasarte, C. (Carmen)|||/items/f1d61c19-1753-4442-a3fd-cc90220e84a0 Tomasi, M.L. (María L.)|||/items/ddfc4380-6698-4ccc-8642-72593b1b15e1 Avila, M.A. (Matías Antonio)|||/items/3ad9abbb-c18d-445b-86cf-cb76be15419f Feo, F. (Francesco)|||/items/99bd4be9-e6a1-43aa-8070-fe350bf4d9a7 Pascale, R.M. (Rosa M.)|||/items/8bc06856-fd21-4dd5-80c4-c8fff8aac3ad |
| author |
Simile, M.M. (María M.)|||/items/01afd25c-f5fa-4ff3-92db-75dce6789ad8 |
| author_facet |
Simile, M.M. (María M.)|||/items/01afd25c-f5fa-4ff3-92db-75dce6789ad8 Latte, G. (Gavinella)|||/items/1cd0beea-30dd-48ee-a6aa-03feaac05bf1 Demartis, M.I. (María I.)|||/items/a1d5abf8-3d62-4f96-85f5-79b53728c2de Brozzetti, S. (Stefania)|||/items/56a0b227-78fc-4fa4-a7aa-901439ce28c6 Calvisi, D.F. (Diego F.)|||/items/f1fd12a7-edff-43c9-a8a8-425bd3a0d865 Porcu, A. (Alberto)|||/items/a66c4daf-5f11-457a-9ba0-bde71133d46c Feo, C.F. (Claudio F.)|||/items/7d78d8fc-c7c2-43c3-9549-7c9fcbbf6bec Seddaiu, M.A. (María A.)|||/items/172dfdd3-a500-4368-8c7c-cd00532ebc19 Daino, L. (Lucia)|||/items/6d5efc12-1684-4fbf-a119-8ee6e3611da7 Berasain-Lasarte, C. (Carmen)|||/items/f1d61c19-1753-4442-a3fd-cc90220e84a0 Tomasi, M.L. (María L.)|||/items/ddfc4380-6698-4ccc-8642-72593b1b15e1 Avila, M.A. (Matías Antonio)|||/items/3ad9abbb-c18d-445b-86cf-cb76be15419f Feo, F. (Francesco)|||/items/99bd4be9-e6a1-43aa-8070-fe350bf4d9a7 Pascale, R.M. (Rosa M.)|||/items/8bc06856-fd21-4dd5-80c4-c8fff8aac3ad |
| author_role |
author |
| author2 |
Latte, G. (Gavinella)|||/items/1cd0beea-30dd-48ee-a6aa-03feaac05bf1 Demartis, M.I. (María I.)|||/items/a1d5abf8-3d62-4f96-85f5-79b53728c2de Brozzetti, S. (Stefania)|||/items/56a0b227-78fc-4fa4-a7aa-901439ce28c6 Calvisi, D.F. (Diego F.)|||/items/f1fd12a7-edff-43c9-a8a8-425bd3a0d865 Porcu, A. (Alberto)|||/items/a66c4daf-5f11-457a-9ba0-bde71133d46c Feo, C.F. (Claudio F.)|||/items/7d78d8fc-c7c2-43c3-9549-7c9fcbbf6bec Seddaiu, M.A. (María A.)|||/items/172dfdd3-a500-4368-8c7c-cd00532ebc19 Daino, L. (Lucia)|||/items/6d5efc12-1684-4fbf-a119-8ee6e3611da7 Berasain-Lasarte, C. (Carmen)|||/items/f1d61c19-1753-4442-a3fd-cc90220e84a0 Tomasi, M.L. (María L.)|||/items/ddfc4380-6698-4ccc-8642-72593b1b15e1 Avila, M.A. (Matías Antonio)|||/items/3ad9abbb-c18d-445b-86cf-cb76be15419f Feo, F. (Francesco)|||/items/99bd4be9-e6a1-43aa-8070-fe350bf4d9a7 Pascale, R.M. (Rosa M.)|||/items/8bc06856-fd21-4dd5-80c4-c8fff8aac3ad |
| author2_role |
author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
Hepatocarcinogenesis Stem cells Progression Gene expression profile Yap targets |
| topic |
Hepatocarcinogenesis Stem cells Progression Gene expression profile Yap targets |
| description |
Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1- tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of YAP1, CTGF, 14–3–3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells. |
| publishDate |
2016 |
| dc.date.none.fl_str_mv |
2016 2016-01-23 2016 2016-01-23 2019 2019-04-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
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info:eu-repo/semantics/article |
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article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/56666 |
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https://hdl.handle.net/10171/56666 |
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Inglés eng |
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Inglés |
| language |
eng |
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open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
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Impact Journals |
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Impact Journals |
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reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
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Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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