Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, 615 Charles E. Young Dr. S., Los Angeles, California, 90095.
Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China.
J Orthop Res. 2019 Feb;37(2):510-521. doi: 10.1002/jor.24189. Epub 2019 Jan 3.
Synovial sarcomas hold a low genomic complexity, making it distinct from other types of soft-tissue sarcomas. Many studies focused on targeting the SS18-SSX fusion protein, which presents in over 90% of human synovial sarcomas. This protein acts as an oncogenic promoter in the tumorigenesis of synovial sarcomas, making it an ideal therapeutic target. However, to date there have been no effective strategies targeting SS18-SSX for the treatment of synovial sarcomas. Therefore, it is an urgent need to identify alternative therapeutic targets. More recently, CDK9, a protein involved in RNA transcription regulation, has been investigated for its role in the pathogenesis of cancer. However, the expression and function of CDK9 in synovial sarcomas remains to be elucidated. In the present study, we found that CDK9 was to be largely localized to the cell nucleus, and highly expressed in all tested human synovial sarcoma cell lines and over 90% of human sarcoma tissue microarray samples. High-CDK9 expression was associated with a poorer patient prognosis of human sarcomas. Inhibition of CDK9, with either siRNA or a CDK9 inhibitor, prevented synovial sarcoma cell growth and proliferation in a dose-dependent manner. This was also accompanied with a reduction in the phosphorylation of RNA polymerase II and an increase in the expression of anti-apoptotic proteins. Moreover, CDK9 inhibition decreased sarcoma cell spheroid formation and cell motility. Collectively, these findings highlight the importance of CDK9 in human synovial sarcoma cell growth and proliferation. Therefore, CDK9 may represent a promising target for the treatment of synovial sarcomas. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:510-521, 2019.
滑膜肉瘤的基因组复杂性较低，这使其有别于其他类型的软组织肉瘤。许多研究都集中在针对 SS18-SSX 融合蛋白上，该蛋白存在于超过 90%的人类滑膜肉瘤中。这种蛋白质在滑膜肉瘤的肿瘤发生中充当致癌促进剂，使其成为理想的治疗靶标。但是，迄今为止，尚无针对滑膜肉瘤的 SS18-SSX 的有效治疗策略。因此，迫切需要确定替代的治疗靶标。最近，参与 RNA 转录调节的 CDK9 蛋白已被研究其在癌症发病机制中的作用。但是，CDK9 在滑膜肉瘤中的表达和功能仍有待阐明。在本研究中，我们发现 CDK9 主要定位于细胞核中，并且在所有测试的人类滑膜肉瘤细胞系和超过 90%的人类肉瘤组织微阵列样本中均高度表达。高 CDK9 表达与人类肉瘤患者的预后较差相关。用 siRNA 或 CDK9 抑制剂抑制 CDK9，可呈剂量依赖性地阻止滑膜肉瘤细胞的生长和增殖。这也伴随着 RNA 聚合酶 II 磷酸化的减少和抗凋亡蛋白表达的增加。此外，CDK9 抑制降低了肉瘤细胞球体形成和细胞迁移能力。总而言之，这些发现强调了 CDK9 在人类滑膜肉瘤细胞生长和增殖中的重要性。因此，CDK9 可能代表治疗滑膜肉瘤的有希望的靶标。©2018 矫形研究学会。由 Wiley Periodicals，Inc. 出版。J Orthop Res 37:510-521，2019。
