Expression of NKG2D ligands is downregulated by β-catenin signalling and associates with HCC aggressiveness.
Adolescent
Adult
Aged
Aged, 80 and over
Animals
Carcinogenesis
/ genetics
Carcinoma, Hepatocellular
/ genetics
Cohort Studies
Disease Models, Animal
Down-Regulation
/ genetics
Female
GPI-Linked Proteins
/ genetics
Gene Expression Regulation, Neoplastic
Histocompatibility Antigens Class I
/ genetics
Humans
Intercellular Signaling Peptides and Proteins
/ genetics
Intracellular Signaling Peptides and Proteins
/ genetics
Liver Neoplasms
/ genetics
Male
Mice
Mice, Inbred C57BL
Middle Aged
Prognosis
Signal Transduction
/ genetics
Young Adult
beta Catenin
/ metabolism
HCC
NKG2D ligands
hepatocellular carcinoma
β-catenin-signalling
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
18
12
2019
revised:
30
12
2020
accepted:
07
01
2021
pubmed:
24
1
2021
medline:
29
1
2022
entrez:
23
1
2021
Statut:
ppublish
Résumé
The NKG2D system is a potent immunosurveillance mechanism in cancer, wherein the activating NK cell receptor (NKG2D) on immune cells recognises its cognate ligands on tumour cells. Herein, we evaluated the expression of NKG2D ligands in hepatocellular carcinoma (HCC), in both humans and mice, taking the genomic features of HCC tumours into account. The expression of NKG2D ligands (MICA, MICB, ULBP1 and ULBP2) was analysed in large human HCC datasets by Fluidigm TaqMan and RNA-seq methods, and in 2 mouse models (mRNA and protein levels) reproducing the features of both major groups of human tumours. We provide compelling evidence that expression of the MICA and MICB ligands in human HCC is associated with tumour aggressiveness and poor patient outcome. We also found that the expression of ULBP1 and ULBP2 was associated with poor patient outcome, and was downregulated in CTNNB1-mutated HCCs displaying low levels of inflammation and associated with a better prognosis. We also found an inverse correlation between ULBP1/2 expression levels and the expression of β-catenin target genes in patients with HCC, suggesting a role for β-catenin signalling in inhibiting expression. We showed in HCC mouse models that β-catenin signalling downregulated the expression of Rae-1 NKG2D ligands, orthologs of ULBPs, through TCF4 binding. We demonstrate that the expression of NKG2D ligands is associated with aggressive liver tumorigenesis and that the downregulation of these ligands by β-catenin signalling may account for the less aggressive phenotype of CTNNB1-mutated HCC tumours. The NKG2D system is a potent immunosurveillance mechanism in cancer. However, its role in hepatocellular carcinoma development has not been widely investigated. Herein, we should that the expression of NKG2D ligands by tumour cells is associated with a more aggressive tumour subtype.
Sections du résumé
BACKGROUND & AIMS
The NKG2D system is a potent immunosurveillance mechanism in cancer, wherein the activating NK cell receptor (NKG2D) on immune cells recognises its cognate ligands on tumour cells. Herein, we evaluated the expression of NKG2D ligands in hepatocellular carcinoma (HCC), in both humans and mice, taking the genomic features of HCC tumours into account.
METHODS
The expression of NKG2D ligands (MICA, MICB, ULBP1 and ULBP2) was analysed in large human HCC datasets by Fluidigm TaqMan and RNA-seq methods, and in 2 mouse models (mRNA and protein levels) reproducing the features of both major groups of human tumours.
RESULTS
We provide compelling evidence that expression of the MICA and MICB ligands in human HCC is associated with tumour aggressiveness and poor patient outcome. We also found that the expression of ULBP1 and ULBP2 was associated with poor patient outcome, and was downregulated in CTNNB1-mutated HCCs displaying low levels of inflammation and associated with a better prognosis. We also found an inverse correlation between ULBP1/2 expression levels and the expression of β-catenin target genes in patients with HCC, suggesting a role for β-catenin signalling in inhibiting expression. We showed in HCC mouse models that β-catenin signalling downregulated the expression of Rae-1 NKG2D ligands, orthologs of ULBPs, through TCF4 binding.
CONCLUSIONS
We demonstrate that the expression of NKG2D ligands is associated with aggressive liver tumorigenesis and that the downregulation of these ligands by β-catenin signalling may account for the less aggressive phenotype of CTNNB1-mutated HCC tumours.
LAY SUMMARY
The NKG2D system is a potent immunosurveillance mechanism in cancer. However, its role in hepatocellular carcinoma development has not been widely investigated. Herein, we should that the expression of NKG2D ligands by tumour cells is associated with a more aggressive tumour subtype.
Identifiants
pubmed: 33484773
pii: S0168-8278(21)00028-3
doi: 10.1016/j.jhep.2021.01.017
pii:
doi:
Substances chimiques
CTNNB1 protein, human
0
CTNNB1 protein, mouse
0
GPI-Linked Proteins
0
Histocompatibility Antigens Class I
0
Intercellular Signaling Peptides and Proteins
0
Intracellular Signaling Peptides and Proteins
0
MHC class I-related chain A
0
MICB antigen
0
ULBP1 protein, human
0
ULBP2 protein, human
0
beta Catenin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1386-1397Informations de copyright
Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest All authors agree to the submission of the manuscript and affirm that the material submitted for publication has not been reported before and is not under consideration for publication elsewhere. The authors have no conflicts of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details.