RRP8 与免疫浸润有关，是肝细胞癌的一个有前景的治疗靶点。
RRP8, associated with immune infiltration, is a prospective therapeutic target in hepatocellular carcinoma.
机构信息
NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
Key Laboratory of Hepatosplenic Surgery of Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
出版信息
J Cancer Res Clin Oncol. 2024 May 9;150(5):245. doi: 10.1007/s00432-024-05756-9.
BACKGROUND
Ribosomal RNA Processing 8 (RRP8) is a nucleolar Rossman fold-like methyltransferase that exhibits increased expression in many malignant tumours. However, the role of RRP8 in hepatocellular carcinoma (HCC) is still uncertain. We explored the relationships between RRP8 and prognosis and immune infiltration, as well as the putative pathological function and mechanism of RRP8 in HCC.
METHODS
Analysis of RRP8 expression across cancers was performed by using multiple databases. Associations between RRP8 expression and clinicopathological factors were further examined. Gene enrichment analysis was used to identify various putative biological activities and regulatory networks of RRP8 in HCC. The relationship between RRP8 expression and immune infiltration was confirmed by single-sample gene set enrichment analysis (ssGSEA). Univariate and multivariate Cox regression analyses were conducted to assess the impact of clinical variables on patient outcomes. Furthermore, a nomogram was constructed to estimate survival probability based on multivariate Cox regression analysis. Functional validation of RRP8 in HCC was performed with two different systems: doxycycline-inducible shRNA knockdown and CRISPR-Cas9 knockout.
RESULTS
RRP8 was markedly overexpressed in HCC clinical specimens compared to adjacent normal tissues. Further analysis demonstrated that RRP8 was directly connected to multiple clinical characteristics and strongly associated with various immune markers in HCC. Moreover, elevated RRP8 expression indicated an unfavourable prognosis. Our functional studies revealed that both knockdown and knockout of RRP8 dramatically attenuated liver cancer cells to proliferate and migrate. Knockout of RRP8 decreased the phosphorylation of MEK1/2 and β-catenin-(Y654) signalling pathway components; downregulated downstream signalling effectors, including Cyclin D1 and N-cadherin; and upregulated E-cadherin.
CONCLUSIONS
RRP8 is strongly implicated in immune infiltration and could be a potential therapeutic target in HCC.
背景
核糖体 RNA 加工 8（RRP8）是一种核仁罗斯曼折叠样甲基转移酶，在许多恶性肿瘤中表达增加。然而，RRP8 在肝细胞癌（HCC）中的作用尚不确定。我们探讨了 RRP8 与预后和免疫浸润的关系，以及 RRP8 在 HCC 中的潜在病理功能和机制。
方法
使用多个数据库分析 RRP8 在癌症中的表达。进一步检查 RRP8 表达与临床病理因素之间的关系。基因富集分析用于鉴定 RRP8 在 HCC 中的各种潜在生物学活性和调控网络。通过单样本基因集富集分析（ssGSEA）证实 RRP8 表达与免疫浸润的关系。单因素和多因素 Cox 回归分析用于评估临床变量对患者结局的影响。此外，根据多因素 Cox 回归分析构建了一个列线图来估计生存概率。使用两种不同的系统：强力霉素诱导的 shRNA 敲低和 CRISPR-Cas9 敲除，对 HCC 中的 RRP8 进行功能验证。
结果
RRP8 在 HCC 临床标本中明显过表达，与相邻正常组织相比。进一步分析表明，RRP8 与多种临床特征直接相关，并且与 HCC 中的多种免疫标志物强烈相关。此外，RRP8 的高表达预示着预后不良。我们的功能研究表明，RRP8 的敲低和敲除都能显著抑制肝癌细胞的增殖和迁移。RRP8 的敲除降低了 MEK1/2 和 β-catenin-(Y654) 信号通路成分的磷酸化；下调下游信号效应物，包括 Cyclin D1 和 N-cadherin；并上调 E-cadherin。
结论
RRP8 强烈参与免疫浸润，可能是 HCC 的一个潜在治疗靶点。
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