Relationship Between Connexin 43 and Bystander Effect of Suicide Gene System_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

1. Department of General Surgery, Nanfang Hospital, Nanfang Medical College, Guangzhou 510515, China;;
2. Department of Community Medicine and Health Service Management, Public Health College, Guangdong Pharmacy College, Guangzhou 510310, China;;
3. Department of General Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430030, ChinaCorresponding Author： ZOU Sheng-quan， E-mail： sqzou@tjh.tjmu.edu.cn;

Corresponding author：

Keywords：

Connexin 43; Suicide gene; Bystander effect; Bile duct tumor; Gene therapy

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Objective 　 To observe the influence of connexin 43 (Cx43) on bystander effects induced by cytosine deaminase (CD) and herpes simplex virus thymidine kinase (HSV-tk) coexpression suicide genes system in human cholangiocarcinoma QBC939 cells and transplantation tumors in nude mice.
Methods 　In vitro, the CD+tk+ and CD+tk+Cx+ cells were respectively treated with 5-fluorocytosine (5-FC) and ganciclovir (GCV). The cytotoxic efficacy was evaluated by microculture tetrajolium test (MTT) method. In order to investigate the influence of Cx43 on bystander effects, the volumes of transplantation tumors of the CD+tk+ and CD+tk+Cx+ cells were measured before and after application of 5-FC and GCV.
Results 　CD and tk gene were stably expressed in transfected QBC939 cells. Increasing expression of Cx43 was determined by testing for the presence of Cx43 mRNA by RT-PCR and the presence of Cx43 protein by Western blot in CD+tk+Cx+ cells. The killing effect of 5-FC and GCV on CD+tk+Cx+ cells was more effective than that on CD+tk+ cells both in vitro and in vivo.
Conclusion 　Double suicide genes system CD/5-FC+tk/GCV could induce remarkable killing effect on cholangiocarcinoma cells in vitro and transplantation tumors in vivo. The cotransfection of Cx43 gene is able to enhance the bystander effects and the inhibition of carcinoma cells.

Citation： DONG Jingqing,LIU Maoling,ZOU Shengquan. Relationship Between Connexin 43 and Bystander Effect of Suicide Gene System. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2008, 15(8): 583-588. doi: Copy

1.	严春寅, 陈卫国, 浦金贤，等. 全反式维甲酸增强雄激素非依赖性前列腺癌自杀基因治疗旁观者效应的实验研究 [Ｊ]. 中华泌尿外科杂志, 2007; 28(4)∶ 274.
2.	曾赵军, 胡维新, 罗赛群，等. Tet-On调节的自杀基因对人乳腺癌细胞的体外杀伤和旁观者效应研究 [Ｊ]. 实用肿瘤杂志, 2006； 21(4)∶ 330.
3.	李梅生, 梁力建, 黄洁夫，等. HSV-tk/CD融合基因杀伤人胆管癌QBC939的体内实验 [Ｊ]. 中国普外基础与临床杂志, 2005; 12(6)∶ 581.
4.	江永浩, 叶钢, 罗顺文，等. HSV-TK/GCV系统对鼠膀胱癌远距离旁观者效应的实验研究 [Ｊ]. 四川医学, 2005; 26(4)∶370.
5.	王继兵, 葛坚, 段山，等. HSV-tk/GCV系统对人Tenon囊成纤维细胞的旁观者效应及其机制研究 [Ｊ]. 眼科研究, 2006; 24(3)∶ 281.
6.	王安训, 黄洪章. 全反式维甲酸提高HSV-TK/GCV系统治疗舌鳞癌旁观者效应的研究 [Ｊ]. 中华口腔医学杂志, 2003; 38(1)∶ 24.
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9.	Yazawa K, Fisher WE, Brunicardi FC. Current progress in suicide gene therapy for cancer [Ｊ]. World J Surg, 2002; 26(7)∶ 783.
10.	Brade AM, Szmitko P, Ngo D, et al. Heat-directed suicide gene therapy for breast cancer [Ｊ]. Cancer Gene Ther, 2003； 10(4)∶ 294.
11.	Misumi M, Suzuki T, Moriuchi S, et al. In vitro thymidine kinase/ganciclovir-based suicide gene therapy using replication defective herpes simplex virus-1 against leukemic B-cell malignancies (MCL, HCL, B-CLL) [Ｊ]. Leuk Res, 2003; 27(8)∶ 695.
12.	Thust R, Tomicic MT, Grabner R, et al. Cytogenetic detection of a trans-species bystander effect: induction of sister chromatid exchanges in murine 3T3 cells by ganciclovir metabolized in HSV thymidine kinase gene-transfected Chinese hamster ovary cells [Ｊ]. Mutagenesis, 2004； 19(1)∶ 27.
13.	Asklund T, Appelskog IB, Ammerpohl O, et al. Gap junction mediated bystander effect in primary cultures of human malignant gliomas with recombinant expression of the HSV-tk gene [Ｊ]. Exp Cell Res, 2003; 284(2)∶ 185.
14.	Hajri A, Wack S, Lehn P, et al. Combined suicide gene therapy for pancreatic peritoneal carcinomatosis using BGTC liposomes [Ｊ]. Cancer Gene Ther, 2004； 11(1)∶ 16.
15.	Burrows FJ, Gore M, Smiley WR, et al. Purified herpes simplex virus thymidine kinase retroviral particles: Ⅲ. Characterization of bystander killing mechanisms in transfected tumor cells [Ｊ]. Cancer Gene Ther, 2002; 9(1)∶ 87.
16.	李学东, 尚西亮, 傅华群，等. 三七总皂甙对大鼠肝卵圆细胞增殖肝脏CX/GJIC的影响 [Ｊ]. 江西医学院学报, 2006; 46(2)∶ 12.
17.	曹玉文, 陆天才, 潘晓琳，等. 间隙连接蛋白表达与宫颈原位癌生长发展的相关性研究 [Ｊ]. 癌症, 2005; 24(5)∶ 567.
18.	夏之柏, 浦佩玉, 王广秀，等. 转染连接蛋白基因对胶质瘤细胞细胞间隙连接通讯及其生长变化的研究 [J]. 中华实验外科杂志, 2003; 20(7)∶ 644.
19.	黄光琦, 宋毅, 张洁，等. 丹参酮ⅡA增强HSV-tk/GCV旁观者效应及其与Cx43 mRNA表达的关系 [Ｊ]. 中华肿瘤杂志, 2004; 26(3)∶ 146.
20.	Agard C, Ligeza C, Dupas B, et al. Immune-dependent distant bystander effect after adenovirus-mediated suicide gene transfer in a rat model of liver colorectal metastasis [Ｊ]. Cancer Gene Ther, 2001; 8(2)∶ 128.

1. 　严春寅, 陈卫国, 浦金贤，等. 全反式维甲酸增强雄激素非依赖性前列腺癌自杀基因治疗旁观者效应的实验研究 [Ｊ]. 中华泌尿外科杂志, 2007; 28(4)∶ 274.
2. 　曾赵军, 胡维新, 罗赛群，等. Tet-On调节的自杀基因对人乳腺癌细胞的体外杀伤和旁观者效应研究 [Ｊ]. 实用肿瘤杂志, 2006； 21(4)∶ 330.
3. 　李梅生, 梁力建, 黄洁夫，等. HSV-tk/CD融合基因杀伤人胆管癌QBC939的体内实验 [Ｊ]. 中国普外基础与临床杂志, 2005; 12(6)∶ 581.
4. 　江永浩, 叶钢, 罗顺文，等. HSV-TK/GCV系统对鼠膀胱癌远距离旁观者效应的实验研究 [Ｊ]. 四川医学, 2005; 26(4)∶370.
5. 　王继兵, 葛坚, 段山，等. HSV-tk/GCV系统对人Tenon囊成纤维细胞的旁观者效应及其机制研究 [Ｊ]. 眼科研究, 2006; 24(3)∶ 281.
6. 　王安训, 黄洪章. 全反式维甲酸提高HSV-TK/GCV系统治疗舌鳞癌旁观者效应的研究 [Ｊ]. 中华口腔医学杂志, 2003; 38(1)∶ 24.
7. 　曹玉文, 陆天才. 细胞间隙连接与肿瘤 [Ｊ]. 石河子大学学报（自然科学版）, 2004; 22(4)∶ 364.
8. 　J.萨姆布鲁克, E.F.弗里奇主编. 黄培堂译. 分子克隆实验指南 [M]. 第2版. 北京：科学出版社， 1992∶672~690, 888~898.
9. 　Yazawa K, Fisher WE, Brunicardi FC. Current progress in suicide gene therapy for cancer [Ｊ]. World J Surg, 2002; 26(7)∶ 783.
10. 　 Brade AM, Szmitko P, Ngo D, et al. Heat-directed suicide gene therapy for breast cancer [Ｊ]. Cancer Gene Ther, 2003； 10(4)∶ 294.
11. 　Misumi M, Suzuki T, Moriuchi S, et al. In vitro thymidine kinase/ganciclovir-based suicide gene therapy using replication defective herpes simplex virus-1 against leukemic B-cell malignancies (MCL, HCL, B-CLL) [Ｊ]. Leuk Res, 2003; 27(8)∶ 695.
12. 　Thust R, Tomicic MT, Grabner R, et al. Cytogenetic detection of a trans-species bystander effect: induction of sister chromatid exchanges in murine 3T3 cells by ganciclovir metabolized in HSV thymidine kinase gene-transfected Chinese hamster ovary cells [Ｊ]. Mutagenesis, 2004； 19(1)∶ 27.
13. 　Asklund T, Appelskog IB, Ammerpohl O, et al. Gap junction mediated bystander effect in primary cultures of human malignant gliomas with recombinant expression of the HSV-tk gene [Ｊ]. Exp Cell Res, 2003; 284(2)∶ 185.
14. 　Hajri A, Wack S, Lehn P, et al. Combined suicide gene therapy for pancreatic peritoneal carcinomatosis using BGTC liposomes [Ｊ]. Cancer Gene Ther, 2004； 11(1)∶ 16.
15. 　Burrows FJ, Gore M, Smiley WR, et al. Purified herpes simplex virus thymidine kinase retroviral particles: Ⅲ. Characterization of bystander killing mechanisms in transfected tumor cells [Ｊ]. Cancer Gene Ther, 2002; 9(1)∶ 87.
16. 　李学东, 尚西亮, 傅华群，等. 三七总皂甙对大鼠肝卵圆细胞增殖肝脏CX/GJIC的影响 [Ｊ]. 江西医学院学报, 2006; 46(2)∶ 12.
17. 　曹玉文, 陆天才, 潘晓琳，等. 间隙连接蛋白表达与宫颈原位癌生长发展的相关性研究 [Ｊ]. 癌症, 2005; 24(5)∶ 567.
18. 　夏之柏, 浦佩玉, 王广秀，等. 转染连接蛋白基因对胶质瘤细胞细胞间隙连接通讯及其生长变化的研究 [J]. 中华实验外科杂志, 2003; 20(7)∶ 644.
19. 　黄光琦, 宋毅, 张洁，等. 丹参酮ⅡA增强HSV-tk/GCV旁观者效应及其与Cx43 mRNA表达的关系 [Ｊ]. 中华肿瘤杂志, 2004; 26(3)∶ 146.
20. 　Agard C, Ligeza C, Dupas B, et al. Immune-dependent distant bystander effect after adenovirus-mediated suicide gene transfer in a rat model of liver colorectal metastasis [Ｊ]. Cancer Gene Ther, 2001; 8(2)∶ 128.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Relationship Between Connexin 43 and Bystander Effect of Suicide Gene System

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