Abstract：
ERCC2 plays a pivotal role in DNA damage repair, however, its specific function in cancer remains elusive. In this study, we made a significant breakthrough by discovering a substantial upregulation of ERCC2 expression in glioblastoma (GBM) tumor tissue. Moreover, elevated levels of ERCC2 expression were closely associated with poor prognosis. Further investigation into the effects of ERCC2 on GBM revealed that suppressing its expression significantly inhibited malignant growth and migration of GBM cells, while overexpression of ERCC2 promoted tumor cell growth. Through mechanistic studies, we elucidated that inhibiting ERCC2 led to cell cycle arrest in the G0/G1 phase by blocking the CDK2/CDK4/CDK6/Cyclin D1/Cyclin D3 pathway. Notably, we also discovered a direct link between ERCC2 and CDK4, a critical protein in cell cycle regulation. Additionally, we explored the potential of TRAIL, a low-toxicity death ligand cytokine with anticancer properties. Despite the typical resistance of GBM cells to TRAIL, tumor cells undergoing cell cycle arrest exhibited significantly enhanced sensitivity to TRAIL. Therefore, we devised a combination strategy, employing TRAIL with the nanoparticle DMC-siERCC2, which effectively suppressed the GBM cell proliferation and induced apoptosis. In summary, our study suggests that targeting ERCC2 holds promise as a therapeutic approach to GBM treatment.
摘要：
ERCC2在DNA损伤修复中起关键作用,然而,它在癌症中的特定功能仍然难以捉摸。在这项研究中,我们通过发现胶质母细胞瘤（GBM）肿瘤组织中ERCC2表达的大幅上调，取得了重大突破。此外，ERCC2表达水平升高与不良预后密切相关.对ERCC2对GBM影响的进一步研究表明，抑制其表达显着抑制GBM细胞的恶性生长和迁移，而ERCC2的过表达促进肿瘤细胞生长。通过机械研究，我们阐明,通过阻断CDK2/CDK4/CDK6/CyclinD1/CyclinD3途径,抑制ERCC2导致G0/G1期细胞周期停滞.值得注意的是,我们还发现了ERCC2和CDK4之间的直接联系,CDK4是细胞周期调控的关键蛋白.此外,我们探索了TRAIL的潜力，一种具有抗癌特性的低毒性死亡配体细胞因子。尽管GBM细胞对TRAIL具有典型的抗性，经历细胞周期停滞的肿瘤细胞对TRAIL的敏感性显著增强.因此,我们设计了一个组合策略，采用TRAIL与纳米颗粒DMC-siERCC2，可有效抑制GBM细胞增殖并诱导细胞凋亡。总之,我们的研究表明,靶向ERCC2有望成为GBM治疗的一种治疗方法.
