Connexin 43 SUMOylation improves gap junction functions between liver cancer stem cells and enhances their sensitivity to HSVtk/GCV

Shen,Yimeng; Li,Yanxia; Ma,Xiaofang; Wan,Qiaohao; Jiang,Zhongmin; Liu,Yixin; Zhang,Dianying; Liu,Xiaozhi; Wu,Wenhan

doi:10.3892/ijo.2018.4263

Connexin 43 SUMOylation improves gap junction functions between liver cancer stem cells and enhances their sensitivity to HSVtk/GCV

Authors:
- Yimeng Shen
- Yanxia Li
- Xiaofang Ma
- Qiaohao Wan
- Zhongmin Jiang
- Yixin Liu
- Dianying Zhang
- Xiaozhi Liu
- Wenhan Wu
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Affiliations: Department of General Surgery, Peking University First Hospital, Beijing 100034, P.R. China, Central Laboratory, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China, Department of Pathology, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China, Department of Pathology, Tianjin Central Hospital of Gynecology and Obstetrics, Tianjin 300100, P.R. China, Department of Orthopedics, Peking University People's Hospital, Beijing 100044, P.R. China
Published online on: February 1, 2018 https://doi.org/10.3892/ijo.2018.4263
Pages: 872-880

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Abstract

Connexin 43 (Cx43) can be modified and regulated by small ubiquitin-like modifier (SUMO)1; however, its role in liver cancer stem cells is poorly understood. In this study, we found a significant difference in the expression of Cx43 and SUMO1 between cancer stem cells and non-cancer stem cells in liver cancer. In liver cancer stem cells, Cx43 was almost absent, although the level of SUMO1 was significantly higher than that in non-cancer stem cells. Further experiments confirmed that the conjugated site of Cx43 by SUMO1 was located in Lys-144 and Lys-237, both of which are highly conserved among species. By the co-expression of Cx43 and SUMO1 in cancer stem cells, the gap junction intercellular communication (GJIC) of liver cancer stem cells was obviously improved. Using this feature, we verified whether it could effectively increase the sensitivity of cancer stem cells to the herpes simplex virus 1 thymidine kinase (HSVtk) gene in combination with ganciclovir (GCV), a conventional chemotherapeutic drug, in vitro and in vivo. As expected, increasing the expression of Cx43 SUMOylation in liver cancer stem cells effectively enhanced their sensitivity to HSVtk/GCV. On the whole, this study revealed a novel method which may be used to effectively restore GJIC in cancer stem cells in liver cancer, which enhances their sensitivity to conventional chemotherapeutic drugs.

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