敲低核糖体 RNA 加工蛋白 15 通过抑制 PATZ1 相关的 LAMC2/FAK 通路抑制肝癌细胞迁移。

Knockdown of ribosome RNA processing protein 15 suppresses migration of hepatocellular carcinoma through inhibiting PATZ1-associated LAMC2/FAK pathway.

机构信息

Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China.

Department of Liver and Gall Surgery, The Third Affiliated Hospital of Wenzhou Medical University, 325200, Wenzhou, Zhejiang, China.

出版信息

BMC Cancer. 2024 Mar 12;24(1):334. doi: 10.1186/s12885-024-12065-4.

DOI:10.1186/s12885-024-12065-4

PMID:38475740

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10936014/

Abstract

BACKGROUND

Ribosomal RNA processing protein 15 (RRP15) has been found to regulate the progression of hepatocellular carcinoma (HCC). Nevertheless, the extent to which it contributes to the spread of HCC cells remains uncertain. Thus, the objective of this research was to assess the biological function of RRP15 in the migration of HCC.

METHODS

The expression of RRP15 in HCC tissue microarray (TMA), tumor tissues and cell lines were determined. In vitro, the effects of RRP15 knockdown on the migration, invasion and adhesion ability of HCC cells were assessed by wound healing assay, transwell and adhesion assay, respectively. The effect of RRP15 knockdown on HCC migration was also evaluated in vivo in a mouse model.

RESULTS

Bioinformatics analysis showed that high expression of RRP15 was significantly associated with low survival rate of HCC. The expression level of RRP15 was strikingly upregulated in HCC tissues and cell lines compared with the corresponding controls, and TMA data also indicated that RRP15 was a pivotal prognostic factor for HCC. RRP15 knockdown in HCC cells reduced epithelial-to-mesenchymal transition (EMT) and inhibited migration in vitro and in vivo, independent of P53 expression. Mechanistically, blockade of RRP15 reduced the protein level of the transcription factor POZ/BTB and AT hook containing zinc finger 1 (PATZ1), resulting in decreased expression of the downstream genes encoding laminin 5 subunits, LAMC2 and LAMB3, eventually suppressing the integrin β4 (ITGB4)/focal adhesion kinase (FAK)/nuclear factor κB kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway.

CONCLUSIONS

RRP15 promotes HCC migration by activating the LAMC2/ITGB4/FAK pathway, providing a new target for future HCC treatment.

摘要

背景

核糖体 RNA 加工蛋白 15（RRP15）已被发现可调节肝细胞癌（HCC）的进展。然而，其对 HCC 细胞扩散的贡献程度尚不确定。因此，本研究旨在评估 RRP15 在 HCC 细胞迁移中的生物学功能。

方法

通过 HCC 组织微阵列（TMA）、肿瘤组织和细胞系检测 RRP15 的表达。在体外，通过划痕愈合实验、Transwell 实验和黏附实验分别评估 RRP15 敲低对 HCC 细胞迁移、侵袭和黏附能力的影响。在小鼠模型中还评估了 RRP15 敲低对 HCC 迁移的影响。

结果

生物信息学分析表明，RRP15 高表达与 HCC 患者生存率降低显著相关。与相应对照相比，RRP15 在 HCC 组织和细胞系中的表达水平显著上调，TMA 数据也表明 RRP15 是 HCC 的关键预后因素。在 HCC 细胞中敲低 RRP15 可减少上皮-间充质转化（EMT），并抑制体外和体内迁移，且与 P53 表达无关。在机制上，阻断 RRP15 可降低转录因子 POZ/BTB 和 AT 钩含有锌指 1（PATZ1）的蛋白水平，导致编码层粘连蛋白 5 亚基、LAMC2 和 LAMB3 的下游基因表达减少，最终抑制整合素 β4（ITGB4）/黏着斑激酶（FAK）/核因子 κB κ 轻链增强子的 B 细胞（NF-κB）信号通路。