尽管 DNA 修复机制可以维持基因组完整性，但在癌细胞中，这些机制可能会对治疗效率产生负面影响。通过抑制 DNA 损伤修复来靶向癌细胞的策略已成功用于使用 PARP 抑制剂治疗乳腺癌和卵巢癌。不幸的是，此类策略尚未在肝癌方面取得成果。肝细胞癌（HCC）是最常见的肝癌类型，是一种难治性恶性肿瘤。尽管引导疗法不断发展，但晚期HCC患者的治疗方案仍不能满足当前的需要，且癌症复发和耐药等重大问题仍然存在。在本文中，我们以负责端粒维持的端粒复制蛋白 CTC1 为目标。使用来自 TCGA 和 GTEx 的肿瘤和匹配组织 RNA 测序数据分析了 CTC 表达。在HCC细胞系中，使用q-RT-PCR和Western blotting检测CTC1表达。使用慢病毒质粒实现了 CTC1 的敲除。通过流式细胞术、MTT、球体和集落形成实验分析CTC1沉默对HCC细胞的影响。CTC1在HCC肿瘤样本中显着下调。然而，与亲本组相比，索拉非尼耐药细胞系中的 CTC1 蛋白水平较高。 CTC1 抑制减少了索拉非尼耐药 HCC 细胞系的细胞增殖，并降低了它们的球体和集落形成能力。此外，这些细胞对 G4 稳定剂 RHPS4 和索拉非尼的单一和联合药物治疗更敏感。我们的结果表明，针对索拉非尼耐药 HCC 患者设计的联合疗法可能是针对 CTC1 的可行选择。© 2024。作者，获得 Springer Nature B.V. 的独家许可

Although DNA repair mechanisms function to maintain genomic integrity, in cancer cells these mechanisms may negatively affect treatment efficiency. The strategy of targeting cancer cells via inhibiting DNA damage repair has been successfully used in breast and ovarian cancer using PARP inhibitors. Unfortunately, such strategies have not yet yielded results in liver cancer. Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a treatment-resistant malignancy. Despite the development of guided therapies, treatment regimens for advanced HCC patients still fall short of the current need and significant problems such as cancer relapse with resistance still exist. In this paper, we targeted telomeric replication protein CTC1, which is responsible for telomere maintenance.CTC expression was analyzed using tumor and matched-tissue RNA-sequencing data from TCGA and GTEx. In HCC cell lines, q-RT-PCR and Western blotting were used to detect CTC1 expression. The knock-down of CTC1 was achieved using lentiviral plasmids. The effects of CTC1 silencing on HCC cells were analyzed by flow cytometry, MTT, spheroid and colony formation assays.CTC1 is significantly downregulated in HCC tumor samples. However, CTC1 protein levels were higher in sorafenib-resistant cell lines compared to the parental groups. CTC1 inhibition reduced cell proliferation in sorafenib-resistant HCC cell lines and diminished their spheroid and colony forming capacities. Moreover, these cells were more sensitive to single and combined drug treatment with G4 stabilizer RHPS4 and sorafenib.Our results suggest that targeting CTC1 might be a viable option for combinational therapies designed for sorafenib resistant HCC patients.© 2024. The Author(s), under exclusive licence to Springer Nature B.V.