Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
J Hepatol. 2012 Feb;56(2):381-8. doi: 10.1016/j.jhep.2011.06.017. Epub 2011 Jul 12.
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.
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.
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.
ULBP1 is prevalently expressed in DN to mod-HCC, but loss of its expression correlates with tumor progression and early recurrence.
自然杀伤细胞激活受体 2 型成员 D（NKG2D）及其配体在肿瘤免疫反应中发挥着关键作用。已有研究表明，肿瘤中 NKG2D 配体的表达与肿瘤的消除和患者生存的改善密切相关，但 NKG2D 配体在肝癌（HCC）免疫反应中的作用仍有待阐明。
我们检测了 54 例 HCC 组织和 HCC 细胞系中 NKG2D 配体的表达情况，并分析了 HCC 组织和细胞系中蛋白酶体的表达及蛋白酶体活性抑制对 NKG2D 配体表达的影响。
在发育不良结节（DN）、高分化（高 HCC）和中分化 HCC（中 HCC）中，UL16 结合蛋白 1（ULBP1）主要在肿瘤细胞中表达，而在低分化 HCC（低 HCC）中不表达。令人惊讶的是，ULBP1 阴性 HCC 患者的无复发生存期显著短于 ULBP1 阳性 HCC 患者（p=0.006）。Cox 回归分析显示，ULBP1 表达缺失是早期复发的独立预测因子（p=0.008）。我们证实 ULBP1 在高分化和中分化 HCC 细胞系中表达，但在低分化 HCC 细胞系 KYN-2 中不表达。然而，抑制蛋白酶体活性可显著上调 KYN-2 中 ULBP1 的表达。此外，我们发现 KYN-2 中的 20S 蛋白酶体表达比高分化和中分化 HCC 细胞系更为丰富。
ULBP1 在 DN 到中 HCC 中广泛表达，但表达缺失与肿瘤进展和早期复发相关。
