Department of Trauma and Orthopedics, Beijing University People's Hospital, Beijing 100044, P.R. China.
Department of Orthopedics, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China.
Int J Oncol. 2018 Sep;53(3):1323-1331. doi: 10.3892/ijo.2018.4448. Epub 2018 Jun 21.
The ability of herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) systems to kill tumor cells is partially dependent on the integrity of gap junction intercellular communication (GJIC) of targeted tumor cells. Recent studies have suggested that connexin 43 (Cx43), which serves a role in gap junction-mediated intercellular communication, is regulated by small ubiquitin-like modifiers (SUMOs). However, the roles of these post-translational modifications remain to be elucidated. The present study demonstrated overexpression of SUMO‑conjugating enzyme Ubc9 (Ubc9) protein in osteosarcoma. Silencing Ubc9 by siRNA inhibited osteosarcoma cell proliferation and migration, and significantly increased the sensitivity of cells to HSV-TK/GCV systems both in vitro and in vivo. Further experimentation demonstrated that silencing Ubc9 induced decoupling of SUMO1 from Cx43, generating increased free Cx43 levels, which is important for reconstructing GJIC and recovering cellular functions. In conclusion, the present study revealed a novel method for the effective restoration of GJIC in osteosarcoma cells, which may increase their sensitivity to conventional chemotherapy.
单纯疱疹病毒胸苷激酶/更昔洛韦（HSV-TK/GCV）系统杀伤肿瘤细胞的能力部分依赖于靶肿瘤细胞缝隙连接细胞间通讯（GJIC）的完整性。最近的研究表明，间隙连接介导的细胞间通讯中的连接蛋白 43（Cx43）受小泛素样修饰物（SUMOs）调节。然而，这些翻译后修饰的作用仍有待阐明。本研究表明，骨肉瘤中 SUMO 连接酶 Ubc9（Ubc9）蛋白表达上调。通过 siRNA 沉默 Ubc9 可抑制骨肉瘤细胞的增殖和迁移，并显著增加细胞对 HSV-TK/GCV 系统的敏感性，无论是在体外还是体内。进一步的实验表明，沉默 Ubc9 诱导 SUMO1 与 Cx43 解偶联，产生更多游离的 Cx43 水平，这对于重建 GJIC 和恢复细胞功能很重要。综上所述，本研究揭示了一种有效恢复骨肉瘤细胞 GJIC 的新方法，可能会增加其对常规化疗的敏感性。
