Center for Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China.
Guangdong Provincial Key Laboratory of Biomedical Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China.
Cancer Biol Ther. 2022 Dec 31;23(1):1-14. doi: 10.1080/15384047.2022.2135960.
Sorafenib (SFN) is a multi-kinase inhibitor drug for the treatment of advanced hepatocellular carcinoma (HCC), but its limited efficacy is a major obstacle to the clinical outcomes of patients with HCC. We aimed to explore a novel molecular mechanism underlying the chemosensitivity of HCC to SFN, and to identify a promising therapeutic target for HCC treatment. In this study, bioinformatic analysis revealed that DDX24 was associated with poor survival in HCC cases, and significantly related to the pathways modulating tumor development. DDX24 regulated HCC cell proliferation and migration potentials. Moreover, reduction of DDX24 promoted the sorafenib-mediated inhibition of HCC cell growth and migration, the elevation of sorafenib-induced HCC cell apoptosis. DDX24 overexpression suppressed the inhibitory effect of SFN on cell proliferation and migration and reduced the apoptosis induced by SFN. Further, DDX24, combined with SFN treatment, presented a synergistic enhancement of the sensitivity of SFN to the growth and migration of HCC cells via AKT/ERK and the epithelial-mesenchymal transition (EMT) pathways, and that it modulated apoptosis via the caspase/PARP pathway. Mechanistically, SNORA18 served as a target gene for DDX24, regulating the chemosensitivity of sorafenib-treated HCC cells. Furthermore, SNORA18 knockdown or overexpression could partially reverse the inhibition or elevation of cell viability, colony formation and migration induced by DDX24 in sorafenib-treated HCC cells, respectively. Collectively, our results suggest that DDX24 regulates the chemosensitivity of HCC to SFN by mediating the expression of SNORA18, which may act as an effective therapeutic target for improving SFN efficiency in HCC treatment.
索拉非尼（SFN）是一种多激酶抑制剂药物，用于治疗晚期肝细胞癌（HCC），但其疗效有限是 HCC 患者临床疗效的主要障碍。我们旨在探索 HCC 对 SFN 化疗敏感性的新分子机制，并确定 HCC 治疗的有前途的治疗靶点。在这项研究中，生物信息学分析表明，DDX24 与 HCC 病例的不良生存相关，并且与调节肿瘤发展的途径显着相关。DDX24 调节 HCC 细胞的增殖和迁移潜力。此外，降低 DDX24 促进了索拉非尼介导的 HCC 细胞生长和迁移的抑制作用，提高了索拉非尼诱导的 HCC 细胞凋亡。DDX24 的过表达抑制了 SFN 对细胞增殖和迁移的抑制作用，并降低了 SFN 诱导的细胞凋亡。此外，DDX24 与 SFN 联合治疗通过 AKT/ERK 和上皮间质转化（EMT）途径增强了 SFN 对 HCC 细胞生长和迁移的敏感性，并且通过 caspase/PARP 途径调节了细胞凋亡。在机制上，SNORA18 作为 DDX24 的靶基因，调节了索拉非尼治疗的 HCC 细胞对化疗的敏感性。此外，SNORA18 的敲低或过表达可分别部分逆转 DDX24 在索拉非尼处理的 HCC 细胞中诱导的细胞活力、集落形成和迁移的抑制或升高。总之，我们的研究结果表明，DDX24 通过介导 SNORA18 的表达来调节 HCC 对 SFN 的化疗敏感性，这可能是提高 SFN 在 HCC 治疗中的效率的有效治疗靶点。
Zotero 插件
