Wang Li-Hong, Tsai Hsiao-Chi, Cheng Yu-Che, Lin Chih-Yang, Huang Yuan-Li, Tsai Chun-Hao, Xu Guo-Hong, Wang Shih-Wei, Fong Yi-Chin, Tang Chih-Hsin
Department of Orthopedics, Dongyang People's Hospital, Wenzhou Medical University, Dongyang, China.
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Cancer Lett. 2017 Apr 10;391:28-37. doi: 10.1016/j.canlet.2017.01.013. Epub 2017 Jan 18.
Osteosarcoma is the most common primary solid tumor of bone. It has a high metastatic potential and occurs predominantly in adolescents and young adults. Angiopoietin 2 (Angpt2) is a key regulator in tumor angiogenesis, facilitating tumor growth and metastasis. Connective tissue growth factor (CTGF, also known as CCN2), is a cysteine-rich protein that has been reported to promote metastasis of osteosarcoma. However, the effect of CTGF on Angpt2 regulation and angiogenesis in human osteosarcoma remains largely unknown. We found that overexpression of CTGF in osteosarcoma cells increased Angpt2 production and induced angiogenesis, in vitro and in vivo. Our findings demonstrate that CTGF-enhanced Angpt2 expression and angiogenesis is mediated by the phospholipase C (PLC)/protein kinase C (PKCδ) signaling pathway. Moreover, endogenous microRNA-543 (miR-543) expression was negatively regulated by CTGF via the PLC/PKCδ pathway. We also provide evidence showing clinical significance between CTGF, Angpt2, and miR-543 as well as tumor staging in human osteosarcoma tissue. CTGF may serve as a therapeutic target in the process of osteosarcoma metastasis and angiogenesis.
骨肉瘤是最常见的原发性骨实体瘤。它具有较高的转移潜能，主要发生于青少年和年轻成年人。血管生成素2（Angpt2）是肿瘤血管生成的关键调节因子，促进肿瘤生长和转移。结缔组织生长因子（CTGF，也称为CCN2）是一种富含半胱氨酸的蛋白质，据报道可促进骨肉瘤转移。然而，CTGF对人骨肉瘤中Angpt2调节和血管生成的影响在很大程度上仍不清楚。我们发现，骨肉瘤细胞中CTGF的过表达在体外和体内均增加了Angpt2的产生并诱导了血管生成。我们的研究结果表明，CTGF增强的Angpt2表达和血管生成是由磷脂酶C（PLC）/蛋白激酶C（PKCδ）信号通路介导的。此外，内源性微小RNA-543（miR-543）的表达通过PLC/PKCδ途径受到CTGF的负调控。我们还提供证据表明CTGF、Angpt2和miR-543之间的临床意义以及人骨肉瘤组织中的肿瘤分期。CTGF可能作为骨肉瘤转移和血管生成过程中的治疗靶点。
