Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
J Cell Biochem. 2018 Feb;119(2):2248-2257. doi: 10.1002/jcb.26387. Epub 2017 Oct 18.
Osteosarcoma is a malignant tumor of the skeletal system. The zinc finger transcription factor ZIC2 has been reported to be highly expressed in human cancers. The present study evaluated the effects of ZIC2 and the possible underlying mechanisms in the human osteosarcoma cells. The expression levels of ZIC2 in human fetal osteoblastic cell line (hFOB1.19), osteosarcoma cell lines (U-2OS, SaoS2, and MG63), normal bone tissue, and osteosarcoma tumor were analyzed by Western blot, and real-time quantitative RT-PCR (qRT-PCR). Osteosarcoma cells with either overexpressed ZIC2 or suppressed ZIC2 were analyzed to determine cell viability, colony formation, and cell invasion. The expressions of SHIP2 and PI3K/AKT signal pathway-related proteins were analyzed by Western blot and qRT-PCR. We first showed that ZIC2 is highly expressed in osteosarcoma cells and tissues. Then we demonstrated that overexpression of ZIC2 promoted viability, migration, and invasion of osteosarcoma cells, whereas suppression of ZIC2 showed opposite effects. Furthermore, SHIP2 expression was negatively regulated by ZIC2. Importantly, ZIC2 overexpression activated the PI3K/AKT signal pathway; however, overexpressed SHIP2 inhibited these effects. Lastly, we showed that activation of the PI3K/AKT signal pathway is essential for the effects of ZIC2 on osteosarcoma cells, as the effects of ZIC2 on the osteosarcoma cells were reversed by a PI3K/AKT inhibitor. Overall, ZIC2 is highly expressed in osteosarcoma cells and tissues, and its overexpression promotes viability, invasion of osteosarcoma cells via SHIP2 suppression, and PI3K/AKT activation. Thus, ZIC2 can be considered as a novel drug target for osteosarcoma management.
骨肉瘤是一种骨骼系统的恶性肿瘤。锌指转录因子 ZIC2 已被报道在人类癌症中高度表达。本研究评估了 ZIC2 在人骨肉瘤细胞中的作用及其潜在的机制。通过 Western blot 和实时定量 RT-PCR（qRT-PCR）分析 ZIC2 在人成骨细胞系（hFOB1.19）、骨肉瘤细胞系（U-2OS、SaoS2 和 MG63）、正常骨组织和骨肉瘤肿瘤中的表达水平。分析过表达 ZIC2 或抑制 ZIC2 的骨肉瘤细胞，以确定细胞活力、集落形成和细胞侵袭。通过 Western blot 和 qRT-PCR 分析 SHIP2 和 PI3K/AKT 信号通路相关蛋白的表达。我们首先表明 ZIC2 在骨肉瘤细胞和组织中高度表达。然后我们证明过表达 ZIC2 促进了骨肉瘤细胞的活力、迁移和侵袭，而抑制 ZIC2 则表现出相反的效果。此外，SHIP2 的表达受 ZIC2 的负调控。重要的是，ZIC2 过表达激活了 PI3K/AKT 信号通路；然而，过表达的 SHIP2 抑制了这些作用。最后，我们表明 PI3K/AKT 信号通路的激活对于 ZIC2 对骨肉瘤细胞的作用是必不可少的，因为 PI3K/AKT 抑制剂逆转了 ZIC2 对骨肉瘤细胞的作用。总之，ZIC2 在骨肉瘤细胞和组织中高度表达，其过表达通过抑制 SHIP2 和激活 PI3K/AKT 促进骨肉瘤细胞的活力、侵袭。因此，ZIC2 可以被认为是骨肉瘤治疗的一个新的药物靶点。
