目的:肝细胞癌(HCC)是全球癌症相关死亡率的第三大原因。转移,负责治疗失败,强调了理解入侵和迁移的分子驱动因素的紧迫性。转移的侵袭性和迁移过程的核心是蛋白质Talin1。然而,Talin1参与HCC的作用和潜在机制仍然难以捉摸。
方法:从我们中心接受肝切除术的患者中收集了总共100个HCC标本。通过检测Talin1的表达水平,评价Talin1与HCC发生发展的关系。进行了体外和体内实验以验证talin1在HCC中的特性。进行RNA-seq和生物信息学分析以鉴定talin1的下游信号通路及其对HCC发展的影响。
结果:这里,我们报道了肝癌组织中Talin1mRNA和蛋白水平的升高。同时,Talin1的下调显著降低了肝癌细胞的体外和体内增殖和转移。此外,升高NRG-1,Talin1的下游靶标,增强HCC细胞的转移。更重要的是,Talin1的衰减通过降低NRG1mRNA的稳定性来抑制HCC的进展,因此调节NRG1的表达及其参与介导PI3K/AKT通路。
结论:综合来看,Talin1调节细胞增殖,转移,通过调节NRG1/PI3K/AKT轴,表明Talin1成为治疗HCC的有希望的候选药物。
OBJECTIVE: Hepatocellular carcinoma (HCC) stands as the third leading cause of cancer-related mortality globally. Metastasis, responsible for treatment failures, underscores the urgency to comprehend molecular drivers of invasion and migration. Central to the invasive and migratory processes underlying metastasis is the protein Talin1. However, the role and underlying mechanisms governing Talin1\'s involvement in HCC have remained elusive.
METHODS: A total of 100 HCC specimens were collected from patients who underwent hepatectomy in our center. The expression level of talin1 was measured to evaluate the correlationship of talin1 and the development of HCC. In vitro and in vivo experiments were conducted to verify the characteristic of talin1 in HCC. RNA-seq and bioinformatics analysis were performed to identify the downstream signal pathway of talin1 and their impact on HCC development.
RESULTS: Here, we reported elevated levels of Talin1 mRNA and protein in HCC tissues. Meanwhile, downregulation of Talin1 significantly reduced the HCC cell proliferation and metastasis in vitro and in vivo. Furthermore, elevating NRG-1, a downstream target of Talin1, enhanced metastasis of HCC cells. More importantly, attenuation of Talin1 inhibited HCC progression through decreasing the stabilization of
NRG1 mRNA, consequently regulating the expression of
NRG1 and its involvement in mediating the PI3K/AKT pathway.
CONCLUSIONS: Taken together, Talin1 regulates cellular proliferation, metastasis, and invasiveness by modulating
NRG1/PI3K/AKT axis, suggesting that Talin1 emerges as a promising candidate for treating HCC.