Cadoux Mathilde, Caruso Stefano, Pham Sandrine, Gougelet Angélique, Pophillat Céline, Riou Rozenn, Loesch Robin, Colnot Sabine, Nguyen Công Trung, Calderaro Julien, Celton-Morizur Séverine, Guerra Nadia, Zucman-Rossi Jessica, Desdouets Chantal, Couty Jean-Pierre
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Team Proliferation Stress and Liver Physiopathology, F-75006 Paris, France.
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Functional genomics of solid tumors Team, Labex Immuno-Oncology, Paris, France.
J Hepatol. 2021 Jun;74(6):1386-1397. doi: 10.1016/j.jhep.2021.01.017. Epub 2021 Jan 21.
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.
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.
NKG2D系统是癌症中一种强大的免疫监视机制，免疫细胞上的活化自然杀伤细胞受体（NKG2D）可识别肿瘤细胞上的同源配体。在此，我们在考虑肝细胞癌（HCC）肿瘤基因组特征的情况下，评估了人类和小鼠肝细胞癌中NKG2D配体的表达情况。
通过Fluidigm TaqMan和RNA测序方法，在大型人类HCC数据集中分析NKG2D配体（MICA、MICB、ULBP1和ULBP2）的表达，并在2种重现人类肿瘤主要类型特征的小鼠模型中（分析mRNA和蛋白质水平）进行分析。
我们提供了有力证据，证明人类HCC中MICA和MICB配体的表达与肿瘤侵袭性及患者预后不良相关。我们还发现，ULBP1和ULBP2的表达与患者预后不良相关，且在显示低炎症水平且预后较好的CTNNB1突变型HCC中表达下调。我们还发现，HCC患者中ULBP1/2表达水平与β-连环蛋白靶基因的表达呈负相关，提示β-连环蛋白信号传导在抑制表达中发挥作用。我们在HCC小鼠模型中表明，β-连环蛋白信号传导通过TCF4结合下调了Rae-1 NKG2D配体（ULBPs的直系同源物）的表达。
我们证明，NKG2D配体的表达与侵袭性肝癌发生相关，且β-连环蛋白信号传导对这些配体的下调可能解释了CTNNB1突变型HCC肿瘤侵袭性较低的表型。
NKG2D系统是癌症中一种强大的免疫监视机制。然而，其在肝细胞癌发生发展中的作用尚未得到广泛研究。在此，我们表明肿瘤细胞中NKG2D配体的表达与侵袭性更强的肿瘤亚型相关。
