Highlights
- •The expression of MICA and MICB is associated with HCC tumour aggressiveness and poor patient outcome.
- •The expression of ULBP1 and ULBP2 is associated with poor patient outcome and is downregulated in CTNNB1-mutated HCC.
- •Expression of the mouse Rae-1 NKG2D ligand is regulated by β-catenin signalling via TCF4 in hepatocytes.
- •The expression of KLRK1 (NKG2D) and ULBP1 is associated with immune cell signatures in HCC.
- •Low levels of NKG2D ligand expression in CTNNB1-mutated HCC may account for the less inflamed and less aggressive phenotype of these tumours.
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: January 20, 2021
Accepted:
January 7,
2021
Received in revised form:
December 30,
2020
Received:
December 18,
2019
Identification
Copyright
© 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
