Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan, 410008, China.
Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
J Exp Clin Cancer Res. 2018 Mar 5;37(1):45. doi: 10.1186/s13046-018-0720-8.
Castor zinc finger 1 (CASZ1) plays critical roles in various biological processes and pathologic conditions, including cancer. However, the prognostic importance and biologic functions of CASZ1 in hepatocellular carcinoma (HCC) are still unclear.
qRT-PCR, western blot and immunohistochemistry analyses were used to determine CASZ1 expression in HCC samples and cell lines. The clinical significance of CASZ1 was assessed in two independent study cohorts containing 232 patients with HCC. A series of in vitro and in vivo experiments were performed to explore the role and molecular mechanism of CASZ1 in HCC progression.
Here we report that CASZ1 expression was downregulated in HCC tissues and cell lines. Low CASZ1 expression was closely correlated with aggressive clinicopathological features, poor clinical outcomes and early recurrence of HCC patients. Moreover, overexpression of CASZ1 in HCCLM3 cells significantly inhibited cell proliferation, migration, invasion in vitro and tumor growth and metastasis in vivo, whereas silencing CASZ1 significantly enhanced the above abilities of PLC/PRF/5 cells. Further mechanism study indicated that these phenotypic changes were mediated by MAPK/ERK signaling pathway and involved altered expression of MMP2, MMP9 and cyclinD1. Finally, we proved that CASZ1 exerted its tumor-suppressive effect by directly interacting with RAF1 and reducing the protein stability of RAF1.
Our study for the first time demonstrated that CASZ1 is a tumor suppressor in HCC, which may serve as a novel prognostic predictor and therapeutic target for HCC patients.
CASTOR 锌指蛋白 1（CASZ1）在包括癌症在内的各种生物过程和病理条件中发挥着关键作用。然而，CASZ1 在肝细胞癌（HCC）中的预后意义和生物学功能仍不清楚。
使用 qRT-PCR、western blot 和免疫组织化学分析来确定 HCC 样本和细胞系中 CASZ1 的表达。在包含 232 名 HCC 患者的两个独立研究队列中评估了 CASZ1 的临床意义。进行了一系列体外和体内实验，以探索 CASZ1 在 HCC 进展中的作用和分子机制。
我们报告说，CASZ1 在 HCC 组织和细胞系中表达下调。低 CASZ1 表达与侵袭性临床病理特征、不良临床结局和 HCC 患者的早期复发密切相关。此外，在 HCCLM3 细胞中过表达 CASZ1 显著抑制了体外细胞增殖、迁移和侵袭以及体内肿瘤生长和转移，而沉默 CASZ1 则显著增强了 PLC/PRF/5 细胞的上述能力。进一步的机制研究表明，这些表型变化是由 MAPK/ERK 信号通路介导的，并涉及 MMP2、MMP9 和 cyclinD1 的表达改变。最后，我们证明 CASZ1 通过直接与 RAF1 相互作用并降低 RAF1 的蛋白稳定性来发挥其肿瘤抑制作用。
我们的研究首次表明，CASZ1 是 HCC 的肿瘤抑制因子，它可能作为 HCC 患者的新型预后预测因子和治疗靶点。
