Alterations of the Immunologic Co-Stimulator B7 and TNFR Families Correlate with Hepatocellular Carcinoma Prognosis and Metastasis by Inactivating STAT3
Alterations of the Immunologic Co-Stimulator B7 and TNFR Families Correlate with Hepatocellular Carcinoma Prognosis and Metastasis by Inactivating STAT3
复制标题
免疫共刺激剂 B7 和 TNFR 家族的改变通过灭活 STAT3 与肝细胞癌的预后和转移相关
DOI：
10.3390/ijms20010156
复制
发表时间：
2019-01-01
影响因子：
5.6
通讯作者：
Tang, Juan
中科院分区：
文献类型：
--
作者：
Li, Yi-Ming;Liu, Zhen-Yu;Tang, Juan
免疫抑制检查点受体细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA4) 或程序性死亡 1 (PD-1) 及其同源配体程序性死亡 1 配体 (PD-L1) 的阻断改变了抗肿瘤免疫治疗的格局。 B7 家族和肿瘤坏死因子受体 (TNFR) 超家族通过共刺激和抑制信号转导在 T 细胞激活、耐受和无反应性中发挥着至关重要的作用。研究 B7 和 TNFR 家族的免疫分子景观对于确定有希望的反应候选者至关重要。在此，我们使用 cBioPortal TCGA 数据对 1000 多名患者的 6 个肝细胞癌 (HCC) 数据集中的 B7 和 TNFR 家族基因进行了全面的改变分析。大约 16% 的患者同时存在 B7 和 TNFR 基因改变。 TNFR 基因扩增（1.73-8.82%）比 B7 基因扩增（1.61-2.94%）相对更常见。对 371 个测序样本的分析显示，所有基因均上调：B7 和 TNFR mRNA 分别在 23% 的病例 (86/371) 和 28% 的病例 (105/371) 中上调。启动子甲基化分析表明 B7 和 TNFR 基因调控的表观遗传基础。 B7和TNFR基因的mRNA水平与启动子甲基化状态呈负相关。 B7-H6 表达与较差的总生存率显着相关，并且在基因拷贝数改变的情况下，B7-H6 mRNA 逐渐增加。 B7-H6 过表达与 HCC 的侵袭性临床病理特征和不良预后相关。 HCC 细胞中 B7-H6 的下调显着抑制细胞粘附、增殖、迁移和侵袭。 HCC 细胞中 B7-H6 的敲低可抑制体内肿瘤生长和转移。 B7-H6 通过诱导 MMP-9 表达和 STAT3 激活促进 HCC 转移。 B7-H6 和 STAT3 在增强 HCC 细胞中 MMP-9 启动子活性方面发挥功能重叠作用。这些结果表明，免疫共刺激因子B7和TNFR家族的改变与HCC转移和预后相关，尤其是B7-H6在促进HCC转移中发挥着关键作用。
Blockade of the immunosuppressive checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed death 1 (PD-1) and its cognate ligand, programmed death 1 ligand (PD-L1), has altered the landscape of anti-tumor immunotherapy. B7 family and tumor necrosis factor receptor (TNFR) superfamily play a crucial role in T cell activation, tolerance, and anergy through co-stimulatory and inhibitory signal transduction. Investigating the immune molecular landscapes of the B7 and TNFR families is critical in defining the promising responsive candidates. Herein, we performed comprehensive alteration analysis of the B7 and TNFR family genes across six hepatocellular carcinoma (HCC) datasets with over 1000 patients using cBioPortal TCGA data. About 16% of patients had both B7 and TNFR gene alterations. TNFR gene amplifications were relatively more common (1.73–8.82%) than B7 gene amplifications (1.61–2.94%). Analysis of 371 sequenced samples revealed that all genes were upregulated: B7 and TNFR mRNA were upregulated in 23% of cases (86/371) and 28% of cases (105/371), respectively. Promoter methylation analysis indicated an epigenetic basis for B7 and TNFR gene regulation. The mRNA levels of B7 and TNFR genes were inversely correlated with promoter methylation status. B7-H6 expression was significantly associated with worse overall survival, and B7-H6 mRNA was increased gradually in cases with gene copy number alterations. B7-H6 overexpression was associated with aggressive clinicopathologic features and poor prognosis in HCC. Downregulation of B7-H6 in HCC cells significantly inhibited cell adhesion, proliferation, migration, and invasion. Knockdown of B7-H6 in HCC cells inhibited tumor growth and metastasis in vivo. B7-H6 promoted HCC metastasis via induction of MMP-9 expression and STAT3 activation. B7-H6 and STAT3 performed functional overlapping roles on enhancing the MMP-9 promoter activity in HCC cells. These results suggest that alterations of the immunologic co-stimulator B7 and TNFR families correlate with HCC metastasis and prognosis, and especially B7-H6 plays a critical role in promoting metastasis of HCC.