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Updated: May 31, 2026
Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence
Hiroteru Kamimura1, Satoshi Yamagiwa, Atsunori Tsuchiya
1Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Background & Aims:
The activating receptor natural killer group 2, member D (NKG2D) and its ligands play a crucial role in immune response to tumors. NKG2D ligand expression in tumors has been shown to be associated with tumor eradication and superior patient survival, but the involvement of NKG2D ligands in the immune response against hepatocellular carcinoma (HCC) still remains to be elucidated.
Methods:
We investigated the expression of NKG2D ligands in HCC tissues collected from 54 patients and HCC cell lines. We also examined the proteasome expression and the effect of inhibition of proteasome activity on NKG2D ligand expression in HCC tissues and cell lines.
Results:
In dysplastic nodules (DN), well-differentiated (well-HCC), and moderately-differentiated HCCs (mod-HCC), UL16-binding protein (ULBP) 1 was expressed predominantly in tumor cells, but not in poorly-differentiated HCCs (poor-HCC). Remarkably, recurrence-free survival of patients with ULBP1-negative HCC was significantly shorter than that of patients with ULBP1-positive HCC (p=0.006). Cox regression analysis revealed that loss of ULBP1 expression was an independent predictor of early recurrence (p=0.008). We confirmed that ULBP1 was expressed in the well- and mod-HCC cell lines, but not in the poor-HCC cell line KYN-2. However, inhibition of proteasome activity resulted in significant up-regulation of ULBP1 expression in KYN-2. Moreover, we found that 20S proteasome expression was more abundant in KYN-2 than that in the well- and mod-HCC cell lines.
Conclusions:
ULBP1 is prevalently expressed in DN to mod-HCC, but loss of its expression correlates with tumor progression and early recurrence.
Insights
Loss of ULBP1 expression in hepatocellular carcinoma (HCC) correlates with tumor progression and early recurrence. This suggests ULBP1 may be a prognostic biomarker for HCC patients.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Natural killer group 2, member D (NKG2D) receptor and its ligands are vital in anti-tumor immunity.
- NKG2D ligand expression in tumors is linked to eradication and survival.
- The role of NKG2D ligands in hepatocellular carcinoma (HCC) immunity requires further investigation.
Purpose of the Study:
- To investigate the expression of NKG2D ligands in HCC.
- To determine the correlation between NKG2D ligand expression and patient survival.
- To explore the role of proteasome activity in regulating NKG2D ligand expression in HCC.
Main Methods:
- Analysis of NKG2D ligand expression in 54 HCC tissues and HCC cell lines.
- Examination of proteasome expression.
- Assessment of proteasome inhibition effects on NKG2D ligand expression.
Main Results:
- UL16-binding protein (ULBP) 1 was expressed in dysplastic nodules, well-differentiated, and moderately-differentiated HCCs, but not in poorly-differentiated HCCs.
- Loss of ULBP1 expression was significantly associated with shorter recurrence-free survival and predicted early recurrence.
- Proteasome inhibition upregulated ULBP1 expression in a poorly-differentiated HCC cell line, which had higher 20S proteasome abundance.
Conclusions:
- ULBP1 is frequently expressed in early-stage HCC but its loss correlates with tumor progression.
- Loss of ULBP1 expression is an independent predictor of early recurrence in HCC patients.
- Proteasome activity may regulate ULBP1 expression in HCC.
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