Connexin 43 SUMOylation improves gap junction functions between liver cancer stem cells and enhances their sensitivity to HSVtk/GCV
Connexin 43 SUMOylation improves gap junction functions between liver cancer stem cells and enhances their sensitivity to HSVtk/GCV
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Connexin 43 SUMOylation 改善肝癌干细胞之间的间隙连接功能并增强其对 HSVtk/GCV 的敏感性
DOI：
10.3892/ijo.2018.4263
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发表时间：
2018-03-01
影响因子：
5.2
通讯作者：
Wu, Wenhan
中科院分区：
文献类型：
--
作者：
Shen, Yimeng;Li, Yanxia;Wu, Wenhan
连接蛋白43(Cx43)可被小泛素样修饰物(SUMO)1修饰和调节，但其在肝癌干细胞中的作用尚不清楚。在本研究中，我们发现Cx43和SUMO1在肝癌中的表达在肿瘤干细胞和非肿瘤干细胞中存在显著差异。在肝癌干细胞中，虽然SUMO1的表达水平明显高于非肿瘤干细胞，但Cx43几乎不表达。进一步实验证实，Cx43与SUMO1的结合位点位于Lys-144和Lys-237，这两个位点在物种间高度保守。通过Cx43和SUMO1在肿瘤干细胞中的共表达，肝癌干细胞的缝隙连接细胞间通讯(GJIC)明显改善。利用这一特性，我们在体内外验证了它是否能有效地提高肿瘤干细胞对单纯疱疹病毒1型胸苷激酶(HSVtk)基因的敏感性，并与常规化疗药物更昔洛韦(GCV)联合使用。正如预期的那样，增加Cx43 SUMO在肝癌干细胞中的表达，有效地增强了其对HSVtk/GCV的敏感性。总体而言，本研究揭示了一种新的方法，可以有效地恢复肝癌肿瘤干细胞中的GJIC，增强其对常规化疗药物的敏感性。
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.