MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells
Background & Aims: Cholangiocarcinoma (CCA) is a heterogeneous and lethal malignancy, the molecular origins of which remain poorly understood. MicroRNAs (miRs) target diverse signalling pathways, functioning as potent epigenetic regulators of tran-scriptional output. We aimed to characterise miR...
| Autores: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/65979 |
| Acceso en línea: | https://hdl.handle.net/10171/65979 |
| Access Level: | acceso abierto |
| Palabra clave: | Cholangiocarcinoma Cholangiocytes FoxO1 microRNAs Proliferation |
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MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cellsDuwe, L. (Lea)|||/items/1df65fa7-63f1-4c57-bb9d-7d33879e5cdbMunoz-Garrido, P. (Patricia)|||/items/5791e618-3b5a-4fee-935b-e4ef9a792005Lewinska, M. (Monika)|||/items/1e033557-9622-4746-982f-0fee929aabefLafuente-Barquero, J. (Juan)|||/items/b8c028e6-0270-432b-bf89-151996164af3Satriano, L. (Letizia)|||/items/4dadbe44-845d-4b04-a853-fb105958c197Hogdall, D. (Dan)|||/items/6081a4f3-817c-46c2-8701-082f39fbe2f4Taranta, A. (Andrzej)|||/items/23baccb4-878a-41c7-afca-aaae4f253ff0Nielsen, B.S. (Boye S.)|||/items/5954aa2e-711c-40f5-8fa3-613b29e0d6b8Ghazal, A. (Awaisa)|||/items/cd460a86-08d7-4735-b982-ab350ffaaedaMatter, M.S. (Matthias S.)|||/items/47ce053d-852a-4a42-866d-5ddff37ff20bBanales, J.M. (Jesús M.)|||/items/0c1309ae-e4e4-4e85-b2f1-567a388889d5Aldana, B.I. (Blanca I.)|||/items/d025dc42-f502-4b2b-8960-428adf46c3ffGao, Y.T. (Yu-Tang)|||/items/1309d47b-b519-4f60-96de-558e08f9d0f5Marquardt, J.U. (Jens U.)|||/items/8893339b-8329-4877-b932-062ad496013cRoberts, L.R. (Lewis R.)|||/items/53e58801-8eb8-49f9-9fd2-46b93d01e35bOliveira, R.C. (Rui C.)|||/items/c1955700-d117-489f-8f07-10e795024300Koshiol, J. (Jill)|||/items/33448410-bb90-4f8f-89fd-896df187081dO’Rourke, C.J. (Colm J.)|||/items/087eb514-d64b-470f-92a8-64ed5518c11fAndersen, J.B. (Jesper B.)|||/items/30522278-e252-4feb-9558-84b5c027103aCholangiocarcinomaCholangiocytesFoxO1microRNAsProliferationBackground & Aims: Cholangiocarcinoma (CCA) is a heterogeneous and lethal malignancy, the molecular origins of which remain poorly understood. MicroRNAs (miRs) target diverse signalling pathways, functioning as potent epigenetic regulators of tran-scriptional output. We aimed to characterise miRNome dysregulation in CCA, including its impact on transcriptome homeostasis and cell behaviour.Methods: Small RNA sequencing was performed on 119 resected CCAs, 63 surrounding liver tissues, and 22 normal livers. High -throughput miR mimic screens were performed in three primary human cholangiocyte cultures. Integration of patient tran-scriptomes and miRseq together with miR screening data identified an oncogenic miR for characterization. MiR-mRNA in-teractions were investigated by a luciferase assay. MiR-CRISPR knockout cells were generated and phenotypically characterized in vitro (proliferation, migration, colony, mitochondrial function, glycolysis) and in vivo using subcutaneous xenografts.Results: In total, 13% (140/1,049) of detected miRs were differentially expressed between CCA and surrounding liver tissues, including 135 that were upregulated in tumours. CCA tissues were characterised by higher miRNome heterogeneity and miR biogenesis pathway expression. Unsupervised hierarchical clustering of tumour miRNomes identified three subgroups, including distal CCA-enriched and IDH1 mutant-enriched subgroups. High-throughput screening of miR mimics uncovered 71 miRs that consistently increased proliferation of three primary cholangiocyte models and were upregulated in CCA tissues regardless of anatomical location, among which only miR-27a-3p had consistently increased expression and activity in several cohorts. FoxO signalling was predominantly downregulated by miR-27a-3p in CCA, partially through targeting of FOXO1. MiR-27a knockout increased FOXO1 levels in vitro and in vivo, impeding tumour behaviour and growth.Conclusions: The miRNomes of CCA tissues are highly remodelled, impacting transcriptome homeostasis in part through regulation of transcription factors like FOXO1. MiR-27a-3p arises as an oncogenic vulnerability in CCA.Dadun. Depósito Académico Digital Universidad de Navarra20232023-04-1820232023-01-0120232023-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/65979reponame: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:10171/659792026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells |
| title |
MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells |
| spellingShingle |
MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells Duwe, L. (Lea)|||/items/1df65fa7-63f1-4c57-bb9d-7d33879e5cdb Cholangiocarcinoma Cholangiocytes FoxO1 microRNAs Proliferation |
| title_short |
MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells |
| title_full |
MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells |
| title_fullStr |
MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells |
| title_full_unstemmed |
MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells |
| title_sort |
MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells |
| dc.creator.none.fl_str_mv |
Duwe, L. (Lea)|||/items/1df65fa7-63f1-4c57-bb9d-7d33879e5cdb Munoz-Garrido, P. (Patricia)|||/items/5791e618-3b5a-4fee-935b-e4ef9a792005 Lewinska, M. (Monika)|||/items/1e033557-9622-4746-982f-0fee929aabef Lafuente-Barquero, J. (Juan)|||/items/b8c028e6-0270-432b-bf89-151996164af3 Satriano, L. (Letizia)|||/items/4dadbe44-845d-4b04-a853-fb105958c197 Hogdall, D. (Dan)|||/items/6081a4f3-817c-46c2-8701-082f39fbe2f4 Taranta, A. (Andrzej)|||/items/23baccb4-878a-41c7-afca-aaae4f253ff0 Nielsen, B.S. (Boye S.)|||/items/5954aa2e-711c-40f5-8fa3-613b29e0d6b8 Ghazal, A. (Awaisa)|||/items/cd460a86-08d7-4735-b982-ab350ffaaeda Matter, M.S. (Matthias S.)|||/items/47ce053d-852a-4a42-866d-5ddff37ff20b Banales, J.M. (Jesús M.)|||/items/0c1309ae-e4e4-4e85-b2f1-567a388889d5 Aldana, B.I. (Blanca I.)|||/items/d025dc42-f502-4b2b-8960-428adf46c3ff Gao, Y.T. (Yu-Tang)|||/items/1309d47b-b519-4f60-96de-558e08f9d0f5 Marquardt, J.U. (Jens U.)|||/items/8893339b-8329-4877-b932-062ad496013c Roberts, L.R. (Lewis R.)|||/items/53e58801-8eb8-49f9-9fd2-46b93d01e35b Oliveira, R.C. (Rui C.)|||/items/c1955700-d117-489f-8f07-10e795024300 Koshiol, J. (Jill)|||/items/33448410-bb90-4f8f-89fd-896df187081d O’Rourke, C.J. (Colm J.)|||/items/087eb514-d64b-470f-92a8-64ed5518c11f Andersen, J.B. (Jesper B.)|||/items/30522278-e252-4feb-9558-84b5c027103a |
| author |
Duwe, L. (Lea)|||/items/1df65fa7-63f1-4c57-bb9d-7d33879e5cdb |
| author_facet |
Duwe, L. (Lea)|||/items/1df65fa7-63f1-4c57-bb9d-7d33879e5cdb Munoz-Garrido, P. (Patricia)|||/items/5791e618-3b5a-4fee-935b-e4ef9a792005 Lewinska, M. (Monika)|||/items/1e033557-9622-4746-982f-0fee929aabef Lafuente-Barquero, J. (Juan)|||/items/b8c028e6-0270-432b-bf89-151996164af3 Satriano, L. (Letizia)|||/items/4dadbe44-845d-4b04-a853-fb105958c197 Hogdall, D. (Dan)|||/items/6081a4f3-817c-46c2-8701-082f39fbe2f4 Taranta, A. (Andrzej)|||/items/23baccb4-878a-41c7-afca-aaae4f253ff0 Nielsen, B.S. (Boye S.)|||/items/5954aa2e-711c-40f5-8fa3-613b29e0d6b8 Ghazal, A. (Awaisa)|||/items/cd460a86-08d7-4735-b982-ab350ffaaeda Matter, M.S. (Matthias S.)|||/items/47ce053d-852a-4a42-866d-5ddff37ff20b Banales, J.M. (Jesús M.)|||/items/0c1309ae-e4e4-4e85-b2f1-567a388889d5 Aldana, B.I. (Blanca I.)|||/items/d025dc42-f502-4b2b-8960-428adf46c3ff Gao, Y.T. (Yu-Tang)|||/items/1309d47b-b519-4f60-96de-558e08f9d0f5 Marquardt, J.U. (Jens U.)|||/items/8893339b-8329-4877-b932-062ad496013c Roberts, L.R. (Lewis R.)|||/items/53e58801-8eb8-49f9-9fd2-46b93d01e35b Oliveira, R.C. (Rui C.)|||/items/c1955700-d117-489f-8f07-10e795024300 Koshiol, J. (Jill)|||/items/33448410-bb90-4f8f-89fd-896df187081d O’Rourke, C.J. (Colm J.)|||/items/087eb514-d64b-470f-92a8-64ed5518c11f Andersen, J.B. (Jesper B.)|||/items/30522278-e252-4feb-9558-84b5c027103a |
| author_role |
author |
| author2 |
Munoz-Garrido, P. (Patricia)|||/items/5791e618-3b5a-4fee-935b-e4ef9a792005 Lewinska, M. (Monika)|||/items/1e033557-9622-4746-982f-0fee929aabef Lafuente-Barquero, J. (Juan)|||/items/b8c028e6-0270-432b-bf89-151996164af3 Satriano, L. (Letizia)|||/items/4dadbe44-845d-4b04-a853-fb105958c197 Hogdall, D. (Dan)|||/items/6081a4f3-817c-46c2-8701-082f39fbe2f4 Taranta, A. (Andrzej)|||/items/23baccb4-878a-41c7-afca-aaae4f253ff0 Nielsen, B.S. (Boye S.)|||/items/5954aa2e-711c-40f5-8fa3-613b29e0d6b8 Ghazal, A. (Awaisa)|||/items/cd460a86-08d7-4735-b982-ab350ffaaeda Matter, M.S. (Matthias S.)|||/items/47ce053d-852a-4a42-866d-5ddff37ff20b Banales, J.M. (Jesús M.)|||/items/0c1309ae-e4e4-4e85-b2f1-567a388889d5 Aldana, B.I. (Blanca I.)|||/items/d025dc42-f502-4b2b-8960-428adf46c3ff Gao, Y.T. (Yu-Tang)|||/items/1309d47b-b519-4f60-96de-558e08f9d0f5 Marquardt, J.U. (Jens U.)|||/items/8893339b-8329-4877-b932-062ad496013c Roberts, L.R. (Lewis R.)|||/items/53e58801-8eb8-49f9-9fd2-46b93d01e35b Oliveira, R.C. (Rui C.)|||/items/c1955700-d117-489f-8f07-10e795024300 Koshiol, J. (Jill)|||/items/33448410-bb90-4f8f-89fd-896df187081d O’Rourke, C.J. (Colm J.)|||/items/087eb514-d64b-470f-92a8-64ed5518c11f Andersen, J.B. (Jesper B.)|||/items/30522278-e252-4feb-9558-84b5c027103a |
| author2_role |
author author author author author 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 |
Cholangiocarcinoma Cholangiocytes FoxO1 microRNAs Proliferation |
| topic |
Cholangiocarcinoma Cholangiocytes FoxO1 microRNAs Proliferation |
| description |
Background & Aims: Cholangiocarcinoma (CCA) is a heterogeneous and lethal malignancy, the molecular origins of which remain poorly understood. MicroRNAs (miRs) target diverse signalling pathways, functioning as potent epigenetic regulators of tran-scriptional output. We aimed to characterise miRNome dysregulation in CCA, including its impact on transcriptome homeostasis and cell behaviour.Methods: Small RNA sequencing was performed on 119 resected CCAs, 63 surrounding liver tissues, and 22 normal livers. High -throughput miR mimic screens were performed in three primary human cholangiocyte cultures. Integration of patient tran-scriptomes and miRseq together with miR screening data identified an oncogenic miR for characterization. MiR-mRNA in-teractions were investigated by a luciferase assay. MiR-CRISPR knockout cells were generated and phenotypically characterized in vitro (proliferation, migration, colony, mitochondrial function, glycolysis) and in vivo using subcutaneous xenografts.Results: In total, 13% (140/1,049) of detected miRs were differentially expressed between CCA and surrounding liver tissues, including 135 that were upregulated in tumours. CCA tissues were characterised by higher miRNome heterogeneity and miR biogenesis pathway expression. Unsupervised hierarchical clustering of tumour miRNomes identified three subgroups, including distal CCA-enriched and IDH1 mutant-enriched subgroups. High-throughput screening of miR mimics uncovered 71 miRs that consistently increased proliferation of three primary cholangiocyte models and were upregulated in CCA tissues regardless of anatomical location, among which only miR-27a-3p had consistently increased expression and activity in several cohorts. FoxO signalling was predominantly downregulated by miR-27a-3p in CCA, partially through targeting of FOXO1. MiR-27a knockout increased FOXO1 levels in vitro and in vivo, impeding tumour behaviour and growth.Conclusions: The miRNomes of CCA tissues are highly remodelled, impacting transcriptome homeostasis in part through regulation of transcription factors like FOXO1. MiR-27a-3p arises as an oncogenic vulnerability in CCA. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2023-04-18 2023 2023-01-01 2023 2023-01-01 |
| 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/10171/65979 |
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https://hdl.handle.net/10171/65979 |
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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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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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