Department of Orthopedics, Zhongnan Hospital of Wuhan University, China.
Department of Orthopedics, Zhongnan Hospital of Wuhan University, China.
Biomed Pharmacother. 2018 Oct;106:1396-1403. doi: 10.1016/j.biopha.2018.07.104. Epub 2018 Jul 23.
Osteosarcoma is the most common primary bone malignancy, mainly occurring in children and adolescents. Cytoskeleton-associated protein 2 (CKAP2), which plays important roles in cell proliferation, has been reported to be overexpressed in diverse human cancers. In the present study, we aimed at exploring the expression and functions of CKAP2 in osteosarcoma. The mRNA and protein expression of CKAP2 was analyzed on collected osteosarcoma and control bone cyst tissues. The results indicated that CKAP2 expression was remarkably elevated in osteosarcoma tissues compared with bone cysts tissues. The expression level of CKAP2 in osteosarcoma was associated with overall survival, tumor size and tumor stage. In addition, down-regulation of CKAP2 by RNA interference in osteosarcoma cell lines, MG63 and SW1353, caused a remarkable inhibition in cell proliferation in vitro and xenograft growth in nude mice. Silencing of CKAP2 also significantly induced G0/G1 arrest and cell apoptosis of osteosarcoma cells. Furthermore, phosphorylation levels of Janus kinase 2 (JAK2) and Signal transducers and activators of transcription 3 (STAT3) were significantly reduced in CKAP2 knockdown cells. The expression of downstream targets of JAK2/STAT3 signaling, Cyclin D1, Bcl-2 and survivin, was also decreased in CKAP2 knockdown cells. Such aberrations can be rescued by re-expression of RNAi-resistant CKAP2. Collectively, the present study indicates that CKAP2 is a potential oncogene by targeting JAK2/STAT3 signaling, and that CKAP2 may serve as a novel target for osteosarcoma therapy.
骨肉瘤是最常见的原发性骨恶性肿瘤，主要发生于儿童和青少年。细胞骨架相关蛋白 2（CKAP2）在细胞增殖中发挥重要作用，据报道在多种人类癌症中过表达。在本研究中，我们旨在探讨 CKAP2 在骨肉瘤中的表达和功能。分析了收集的骨肉瘤和对照骨囊肿组织中 CKAP2 的 mRNA 和蛋白表达。结果表明，CKAP2 在骨肉瘤组织中的表达明显高于骨囊肿组织。CKAP2 在骨肉瘤中的表达水平与总生存期、肿瘤大小和肿瘤分期相关。此外，在骨肉瘤细胞系 MG63 和 SW1353 中通过 RNA 干扰下调 CKAP2 导致体外细胞增殖和裸鼠异种移植生长显著抑制。CKAP2 的沉默还显著诱导骨肉瘤细胞的 G0/G1 期阻滞和细胞凋亡。此外，CKAP2 敲低细胞中 Janus 激酶 2（JAK2）和信号转导子和转录激活子 3（STAT3）的磷酸化水平显著降低。JAK2/STAT3 信号下游靶标 Cyclin D1、Bcl-2 和 survivin 的表达也在 CKAP2 敲低细胞中降低。通过重新表达 RNAi 抗性 CKAP2 可以挽救这些异常。总之，本研究表明 CKAP2 通过靶向 JAK2/STAT3 信号是一种潜在的癌基因，CKAP2 可能成为骨肉瘤治疗的新靶点。
