Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
Wenzhou Medical University Eye Hospital and School of Biomedical Engineering, China.
Mol Oncol. 2021 Nov;15(11):3184-3202. doi: 10.1002/1878-0261.12980. Epub 2021 Jul 27.
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to a high rate of tumour metastasis and disease recurrence. In physiological conditions, tetraspanins interact with specific partner proteins in tetraspanin-enriched microdomains and regulate their subcellular localization and function. However, the function of Tspan5 in pathological processes, particularly in cancer biology and its clinical significance, are still unclear. Here, we describe that a high expression of Tspan5 is significantly associated with some clinicopathological features including invasive length, vascular invasion, clinical stage and poor overall survival of HCC patients. Alterations of Tspan5 expression by lentivirus transductions in HCC cells demonstrated that Tspan5 promotes wound healing and cell migration in vitro and tumour metastasis of HCC cells in vivo. Mechanistic studies revealed that Tspan5 promoted cell migration and tumour metastasis by increasing the enzymatic maturation of ADAM10 and activating Notch signalling via the increase of the cleavage of the Notch1 receptor catalysed by the γ-secretase complex. Activation of Notch signalling by Tspan5 was shown further to enhance the epithelial-mesenchymal transition (EMT) and actin skeleton rearrangement of tumour cells. In clinical HCC samples, Tspan5 expression is strongly correlated with many key molecules acting in Notch signalling and EMT, highlighting the role of Tspan5 in the regulation of Notch signalling, EMT and tumour metastasis of HCC. Our findings provide new insights into the mechanism of tumour metastasis and disease progression of HCC and may facilitate the development of novel clinical intervention strategies against HCC.
肝细胞癌（HCC）是全球最致命的癌症之一，其肿瘤转移和疾病复发率很高。在生理条件下，四跨膜蛋白与富含四跨膜蛋白的微域中的特定伴侣蛋白相互作用，并调节它们的亚细胞定位和功能。然而，Tspan5 在病理过程中的功能，特别是在癌症生物学及其临床意义方面，仍然不清楚。在这里，我们描述了 Tspan5 的高表达与一些临床病理特征显著相关，包括 HCC 患者的浸润长度、血管侵犯、临床分期和总体生存率较差。通过慢病毒转导改变 HCC 细胞中的 Tspan5 表达，证明 Tspan5 促进了 HCC 细胞的体外伤口愈合和细胞迁移以及体内肿瘤转移。机制研究表明，Tspan5 通过增加 ADAM10 的酶成熟和激活 Notch 信号通路，增加 γ-分泌酶复合物催化的 Notch1 受体裂解，促进细胞迁移和肿瘤转移。Tspan5 激活 Notch 信号通路进一步增强了肿瘤细胞的上皮-间充质转化（EMT）和肌动蛋白骨架重排。在临床 HCC 样本中，Tspan5 的表达与 Notch 信号通路和 EMT 中许多关键分子强烈相关，突出了 Tspan5 在 HCC 中 Notch 信号通路、EMT 和肿瘤转移调控中的作用。我们的发现为 HCC 肿瘤转移和疾病进展的机制提供了新的见解，并可能为开发针对 HCC 的新型临床干预策略提供帮助。
