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

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

doi:10.3892/ijo.2018.4263

Abstract

Connexin43 (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 virus1 thymidine kinase (HSVtk) gene in combination with ganciclovir (GCV), a conventional chemotherapeutic drug, invitro and invivo. 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.

Highlights

Liver cancer is one of the most common malignant tumors of the digestive system [1]
In this study, we first examined the expression of Connexin 43 (Cx43) in liver cancer tissues and adjacent tissues from 8 patients who underwent surgical resection
To date, at least to the best of our knowledge, limited research has been performed into the association between Cx43 and SUMO1 in liver cancer

Summary

Introduction

Liver cancer is one of the most common malignant tumors of the digestive system [1]. In China, the incidence of liver cancer has increased annually due to the persistent high infection rate of hepatitis B virus in the population [2]. The major forms of liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma. There are two rare malignant liver tumors occurring in adolescence, hepatoblastoma and fibrolamellar carcinoma, both developing in a non-cirrhotic liver [3]. The treatment options for liver cancer and its prognosis depend on a number of factors, including tumor size, staging and the extent of liver injury [4]. The overall recurrence rate following resection is 50-60% [6]. Radiotherapy and chemotherapy are often employed, the treatment effects are extremely limited [7]

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