Abstract:
Nuclear pore complex (NPC) embedded in the nuclear envelope, is the only channel for macromolecule nucleocytoplasmic transportation and has important biological functions. However, the deregulation of specific nucleoporins (Nups) and NPC-Nup-based mechanisms and their function in tumour progression remain poorly understood. Here, we aimed to identify the Nups that contribute to HCC progression and metastasis in 729 primary hepatocellular carcinoma (HCC) cases using molecular, cytological, and biochemical techniques. Our results revealed elevated Nup93 expression in HCC tissues, especially in cases with metastasis, and was linked to worse prognosis. Furthermore, Nup93 knockdown suppressed HCC cell metastasis and proliferation, while Nup93 overexpression promoted these activities. We observed that Nup93 promotes HCC metastasis and proliferation by regulating β-catenin translocation. In addition, we found that Nup93 interacted with β-catenin directly, independent of importin. Furthermore, LEF1 and β-catenin facilitated the Nup93-mediated metastasis and proliferation in HCC via a positive feedback loop. Thus, our findings provide novel insights into the mechanisms underlying the Nup93-induced promotion of HCC metastasis and suggest potential therapeutic targets in the LEF1-Nup93-β-catenin pathway for HCC therapeutics.
摘要:
核孔隙复合物(NPC)嵌入在核包膜中,是大分子核质运输的唯一通道,具有重要的生物学功能。然而,特异性核孔蛋白(Nups)和基于NPC-Nup的机制的失调及其在肿瘤进展中的功能仍然知之甚少。这里,我们的目的是确定有助于肝癌进展和转移的Nups729例原发性肝细胞癌(HCC)使用分子,细胞学,和生化技术。我们的结果表明,在肝癌组织中Nup93表达升高,特别是在有转移的情况下,并与预后较差有关。此外,Nup93敲低抑制肝癌细胞的转移和增殖,而Nup93过表达促进了这些活性。我们观察到Nup93通过调节β-catenin易位促进HCC转移和增殖。此外,我们发现Nup93与β-catenin直接相互作用,独立于进口。此外,LEF1和β-catenin通过正反馈回路促进Nup93介导的HCC转移和增殖。因此,我们的研究结果为Nup93诱导的HCC转移促进的潜在机制提供了新的见解,并提示了LEF1-Nup93-β-catenin途径中用于HCC治疗的潜在治疗靶点.