Telomere length is key to hepatocellular ...
Type de document :
Article dans une revue scientifique: Article original
PMID :
URL permanente :
Titre :
Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target.
Auteur(s) :
Ningarhari, Massih [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Caruso, Stefano [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Hirsch, Théo Z [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Bayard, Quentin [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Franconi, Andrea [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Védie, Anne-Laure [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Noblet, Bénédicte [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Blanc, Jean-Frédéric [Auteur]
Bordeaux Research In Translational Oncology [Bordeaux] [BaRITOn]
Amaddeo, Giuliana [Auteur]
Université Paris-Est Créteil Val-de-Marne - Paris 12 [UPEC UP12]
Ganne, Nathalie [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Ziol, Marianne [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Paradis, Valérie [Auteur]
Centre de recherche sur l'Inflammation [CRI (UMR_S_1149 / ERL_8252 / U1149)]
Guettier, Catherine [Auteur]
Calderaro, Julien [Auteur]
Institut Mondor de Recherche Biomédicale [IMRB]
Morcrette, Guillaume [Auteur]
Kim, Youngsoo [Auteur]
Macleod, A. Robert [Auteur]
Nault, Jean-Charles [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Rebouissou, Sandra [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Zucman-Rossi, Jessica [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Caruso, Stefano [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Hirsch, Théo Z [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Bayard, Quentin [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Franconi, Andrea [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Védie, Anne-Laure [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Noblet, Bénédicte [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Blanc, Jean-Frédéric [Auteur]
Bordeaux Research In Translational Oncology [Bordeaux] [BaRITOn]
Amaddeo, Giuliana [Auteur]
Université Paris-Est Créteil Val-de-Marne - Paris 12 [UPEC UP12]
Ganne, Nathalie [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Ziol, Marianne [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Paradis, Valérie [Auteur]
Centre de recherche sur l'Inflammation [CRI (UMR_S_1149 / ERL_8252 / U1149)]
Guettier, Catherine [Auteur]
Calderaro, Julien [Auteur]
Institut Mondor de Recherche Biomédicale [IMRB]
Morcrette, Guillaume [Auteur]
Kim, Youngsoo [Auteur]
Macleod, A. Robert [Auteur]
Nault, Jean-Charles [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Rebouissou, Sandra [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Zucman-Rossi, Jessica [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Titre de la revue :
Journal of Hepatology
Nom court de la revue :
J Hepatol
Numéro :
74
Pagination :
1155-1166
Date de publication :
2021-05
ISSN :
1600-0641
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
Background & aims: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis.
Methods: ...
Lire la suite >Background & aims: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis. Methods: Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model. Results: Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model. Conclusions: Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials. Lay summary: Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides.Lire moins >
Lire la suite >Background & aims: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis. Methods: Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model. Results: Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model. Conclusions: Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials. Lay summary: Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
Université de Lille
Inserm
CHU Lille
Inserm
CHU Lille
Collections :
Date de dépôt :
2024-01-31T22:15:21Z
2024-09-12T13:06:31Z
2024-09-12T13:06:31Z