Department of Anatomy-Histology and Embryology, School of Medicine, University of Patras, Greece.
Department of Hepatobiliary and Pancreatic Surgery, University Hospital of Southampton, United Kingdom.
Pathol Res Pract. 2022 Jul;235:153950. doi: 10.1016/j.prp.2022.153950. Epub 2022 May 23.
Hepatocellular carcinoma (HCC) is a common cause a cancer-related death. Focal adhesions (FAs) represent multiprotein complexes at integrin-mediated cell-extracellular matrix adhesion sites that orchestrate vital cellular functions. The heterotrimeric ILK-PINCH-PARVB (IPP) complex, RSU1, a PINCH binding protein and CTEN, a member of the tensin family of proteins exert a critical role in FAs, where they regulate important cancer related functions such as cell adhesion, migration, proliferation and survival. Previous studies implicate these FA proteins in liver pathophysiology but their detailed role in human HCC is not fully understood. Here in we investigated expression and function of IPP, RSU1 and CTEN in human HCC.
The expression of focal adhesion proteins was studied in human HCC by immunohistochemistry in relation to clinicopathological parameters, previous studied genomic instability markers and patient's survival. Effects on cell proliferation and FA proteins expression upon ILK inhibition and RSU1 silencing were also investigated in HCC in vitro.
IPP complex and CTEN proteins are overexpressed while RSU1 expression is decreased in human HCC. CTEN expression correlates with reduced patients' survival while RSU1 represents an independent favorable prognostic indicator in human HCC. Nuclear ILK expression correlates with markers of genomic instability. Pharmacological targeting of ILK suppresses, while RSU1 silencing promotes cell growth of HCC cells in vitro, while in both experimental conditions expression and/or localization of focal adhesion proteins is deregulated.
Our results suggest that FA signaling is implicated in hepatocellular carcinogenesis with prognostic significance. RSU1 seems to exert tumor suppressive functions in HCC and represents a novel favorable prognostic indicator.
肝细胞癌（HCC）是癌症相关死亡的常见原因。黏着斑（FAs）代表整合素介导的细胞-细胞外基质黏附部位的多蛋白复合物，协调重要的细胞功能。异三聚体 ILK-PINCH-PARVB（IPP）复合物、RSU1（PINCH 结合蛋白）和 CTEN（张力蛋白家族蛋白的成员）在黏着斑中发挥关键作用，调节细胞黏附、迁移、增殖和存活等重要的癌症相关功能。先前的研究表明这些 FA 蛋白在肝病理生理学中发挥作用，但它们在人类 HCC 中的详细作用尚不完全清楚。本研究调查了 IPP、RSU1 和 CTEN 在人类 HCC 中的表达和功能。
通过免疫组织化学研究，我们分析了与临床病理参数、先前研究的基因组不稳定性标记物和患者生存相关的人类 HCC 中黏着斑蛋白的表达。还在 HCC 中研究了 ILK 抑制和 RSU1 沉默对细胞增殖和 FA 蛋白表达的影响。
IPP 复合物和 CTEN 蛋白在人类 HCC 中过表达，而 RSU1 表达减少。CTEN 表达与患者生存时间缩短相关，而 RSU1 则是人类 HCC 的独立预后良好指标。核 ILK 表达与基因组不稳定性标记物相关。ILK 的药物靶向抑制，而 RSU1 沉默促进 HCC 细胞的体外生长，而在这两种实验条件下，黏着斑蛋白的表达和/或定位均失调。
我们的研究结果表明，黏着斑信号转导参与了肝癌的发生发展，并具有预后意义。RSU1 似乎在 HCC 中发挥肿瘤抑制作用，是一种新的预后良好指标。
