TGFβ-induced circLTBP2 predicts a poor prognosis in intrahepatic cholangiocarcinoma and mediates gemcitabine resistance by sponging miR-338-3p

Background & Aims: Intrahepatic cholangiocarcinoma (iCCA) is a deadly cancer worldwide with an increasing incidence and limited therapeutic options. Therefore, there is an urgent need to open the field to new concepts for identifying clinically relevant therapeutic targets and biomarkers. Here,...

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Authors: Louis, Corentin, Ferlier, Tanguy, Leroux, Raffaële, Pineau, Raphaël, Desoteux, Matthis, Papoutsoglou, Panagiotis, Leclerc, Delphine, Angenard, Gaëlle, Vaquero, Javier, Macias, Rocio L.R., Edeline, Julien, Coulouarn, Cédric
Format: article
Status:Published version
Publication Date:2023
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/205749
Online Access:https://hdl.handle.net/2445/205749
Access Level:Open access
Keyword:Càncer de fetge
RNA
Liver cancer
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oai_identifier_str oai:diposit.ub.edu:2445/205749
network_acronym_str ES
network_name_str España
repository_id_str
spelling TGFβ-induced circLTBP2 predicts a poor prognosis in intrahepatic cholangiocarcinoma and mediates gemcitabine resistance by sponging miR-338-3pLouis, CorentinFerlier, TanguyLeroux, RaffaëlePineau, RaphaëlDesoteux, MatthisPapoutsoglou, PanagiotisLeclerc, DelphineAngenard, GaëlleVaquero, JavierMacias, Rocio L.R.Edeline, JulienCoulouarn, CédricCàncer de fetgeRNALiver cancerRNABackground & Aims: Intrahepatic cholangiocarcinoma (iCCA) is a deadly cancer worldwide with an increasing incidence and limited therapeutic options. Therefore, there is an urgent need to open the field to new concepts for identifying clinically relevant therapeutic targets and biomarkers. Here, we explored the role and the clinical relevance of circular RNA (circRNA) circLTBP2 in iCCA.Methods: Transforming growth factor b (TGFb)-regulated circRNAs were identified by dedicated microarrays in human HuCC-T1 iCCA cell line, and their clinical relevance was evaluated in independent cohorts of patients. Gain and loss of function of circLTBP2 combined with functional tests was performed in vitro and in vivo in mice. RNA pulldown, microRNA sequencing, and RNA immunoprecipitation were performed to explore the sponging activity of circLTBP2. Results: CircLTBP2 (has_circ_0032603) was identified as a novel TGFb-induced circRNA in several cholangiocarcinoma cell lines. CircLTBP2 promotes tumour cell proliferation, migration, and resistance to gemcitabine-induced apoptosis in vitro and tumour growth in vivo. Mechanistically, circLTBP2 acts as a competitive RNA regulating notably the activity of the tumour suppressor microRNA miR-338-3p, leading to the overexpression of its pro-metastatic targets. The restoration of miR-338-3p levels in iCCA cells reversed the pro-tumourigenic effects driven by circLTBP2, including the resistance to gemcitabine-induced apoptosis. In addition, circLTBP2 expression predicted a reduced survival, as detected in not only tumour tissues but also serum extracellular vesicles isolated from patients with iCCA.Conclusions: CircLTBP2 is a novel effector of the pro-tumourigenic arm of TGFb and a clinically relevant biomarker easily detected from liquid biopsies in iCCA.Impact and implications: Intrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer with limited therapeutic options. Opening the field to new concepts is urgently needed to improve the survival of patients. Here, we evaluated the role and the clinical relevance of circular RNA. We report that TGFb-induced circLTBP2 contributes to CCA carcinogenesis and may constitute a clinically relevant prognostic biomarker detected in liquid biopsies. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Elsevier BV2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/205749Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.jhepr.2023.100900JHEP Reports, 2023, vol. 5, num. 12, p. 100900https://doi.org/10.1016/j.jhepr.2023.100900cc by-nc-nd (c) Louis, Corentin et al., 2023http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2057492026-05-27T06:46:51Z
dc.title.none.fl_str_mv TGFβ-induced circLTBP2 predicts a poor prognosis in intrahepatic cholangiocarcinoma and mediates gemcitabine resistance by sponging miR-338-3p
title TGFβ-induced circLTBP2 predicts a poor prognosis in intrahepatic cholangiocarcinoma and mediates gemcitabine resistance by sponging miR-338-3p
spellingShingle TGFβ-induced circLTBP2 predicts a poor prognosis in intrahepatic cholangiocarcinoma and mediates gemcitabine resistance by sponging miR-338-3p
Louis, Corentin
Càncer de fetge
RNA
Liver cancer
RNA
title_short TGFβ-induced circLTBP2 predicts a poor prognosis in intrahepatic cholangiocarcinoma and mediates gemcitabine resistance by sponging miR-338-3p
title_full TGFβ-induced circLTBP2 predicts a poor prognosis in intrahepatic cholangiocarcinoma and mediates gemcitabine resistance by sponging miR-338-3p
title_fullStr TGFβ-induced circLTBP2 predicts a poor prognosis in intrahepatic cholangiocarcinoma and mediates gemcitabine resistance by sponging miR-338-3p
title_full_unstemmed TGFβ-induced circLTBP2 predicts a poor prognosis in intrahepatic cholangiocarcinoma and mediates gemcitabine resistance by sponging miR-338-3p
title_sort TGFβ-induced circLTBP2 predicts a poor prognosis in intrahepatic cholangiocarcinoma and mediates gemcitabine resistance by sponging miR-338-3p
dc.creator.none.fl_str_mv Louis, Corentin
Ferlier, Tanguy
Leroux, Raffaële
Pineau, Raphaël
Desoteux, Matthis
Papoutsoglou, Panagiotis
Leclerc, Delphine
Angenard, Gaëlle
Vaquero, Javier
Macias, Rocio L.R.
Edeline, Julien
Coulouarn, Cédric
author Louis, Corentin
author_facet Louis, Corentin
Ferlier, Tanguy
Leroux, Raffaële
Pineau, Raphaël
Desoteux, Matthis
Papoutsoglou, Panagiotis
Leclerc, Delphine
Angenard, Gaëlle
Vaquero, Javier
Macias, Rocio L.R.
Edeline, Julien
Coulouarn, Cédric
author_role author
author2 Ferlier, Tanguy
Leroux, Raffaële
Pineau, Raphaël
Desoteux, Matthis
Papoutsoglou, Panagiotis
Leclerc, Delphine
Angenard, Gaëlle
Vaquero, Javier
Macias, Rocio L.R.
Edeline, Julien
Coulouarn, Cédric
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer de fetge
RNA
Liver cancer
RNA
topic Càncer de fetge
RNA
Liver cancer
RNA
description Background & Aims: Intrahepatic cholangiocarcinoma (iCCA) is a deadly cancer worldwide with an increasing incidence and limited therapeutic options. Therefore, there is an urgent need to open the field to new concepts for identifying clinically relevant therapeutic targets and biomarkers. Here, we explored the role and the clinical relevance of circular RNA (circRNA) circLTBP2 in iCCA.Methods: Transforming growth factor b (TGFb)-regulated circRNAs were identified by dedicated microarrays in human HuCC-T1 iCCA cell line, and their clinical relevance was evaluated in independent cohorts of patients. Gain and loss of function of circLTBP2 combined with functional tests was performed in vitro and in vivo in mice. RNA pulldown, microRNA sequencing, and RNA immunoprecipitation were performed to explore the sponging activity of circLTBP2. Results: CircLTBP2 (has_circ_0032603) was identified as a novel TGFb-induced circRNA in several cholangiocarcinoma cell lines. CircLTBP2 promotes tumour cell proliferation, migration, and resistance to gemcitabine-induced apoptosis in vitro and tumour growth in vivo. Mechanistically, circLTBP2 acts as a competitive RNA regulating notably the activity of the tumour suppressor microRNA miR-338-3p, leading to the overexpression of its pro-metastatic targets. The restoration of miR-338-3p levels in iCCA cells reversed the pro-tumourigenic effects driven by circLTBP2, including the resistance to gemcitabine-induced apoptosis. In addition, circLTBP2 expression predicted a reduced survival, as detected in not only tumour tissues but also serum extracellular vesicles isolated from patients with iCCA.Conclusions: CircLTBP2 is a novel effector of the pro-tumourigenic arm of TGFb and a clinically relevant biomarker easily detected from liquid biopsies in iCCA.Impact and implications: Intrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer with limited therapeutic options. Opening the field to new concepts is urgently needed to improve the survival of patients. Here, we evaluated the role and the clinical relevance of circular RNA. We report that TGFb-induced circLTBP2 contributes to CCA carcinogenesis and may constitute a clinically relevant prognostic biomarker detected in liquid biopsies. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/205749
url https://hdl.handle.net/2445/205749
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.jhepr.2023.100900
JHEP Reports, 2023, vol. 5, num. 12, p. 100900
https://doi.org/10.1016/j.jhepr.2023.100900
dc.rights.none.fl_str_mv cc by-nc-nd (c) Louis, Corentin et al., 2023
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Louis, Corentin et al., 2023
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier BV
publisher.none.fl_str_mv Elsevier BV
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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