Delayed liver regeneration and increased susceptibility to chemical hepatocarcinogenesis in transgenic mice expressing a dominant-negative mutant of connexin32 only in the liver
Delayed liver regeneration and increased susceptibility to chemical hepatocarcinogenesis in transgenic mice expressing a dominant-negative mutant of connexin32 only in the liver
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DOI：
10.1093/carcin/bgh050
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发表时间：
2004-04-01
期刊：
影响因子：
4.7
通讯作者：
Omori, Y
中科院分区：
文献类型：
--
作者：
Dagli, MLZ;Yamasaki, H;Omori, Y
越来越多的体外研究证据表明，间隙连接蛋白连接蛋白可能具有肿瘤抑制功能。我们先前的HeLa细胞双转染实验表明，连接蛋白32（Cx 32）的显性负突变体V139 M可以消除间隙连接细胞间通讯（GJIC）。为了研究Cx32的相同显性阴性突变体是否抑制体内肝细胞之间的GJIC，从而调节细胞增殖和对肝癌发生的易感性，我们用肝脏特异性白蛋白启动子驱动的突变体Cx32基因创建了转基因小鼠。这些小鼠在出生前后发育正常，正如预期的那样，肝脏中的GJIC减少。在转基因小鼠中未观察到任何部位的自发性肿瘤发生率增加。而出乎意料的是，部分肝切除术后肝再生过程中的细胞增殖被推迟了24小时，在转基因小鼠与野生型小鼠相比。相反，转基因雄性小鼠对二乙基亚硝胺诱导的肝癌更敏感，在更短的潜伏期内发生更多的肝脏肿瘤。这些结果表明，GJIC可以协调细胞生长的积极和消极的在体内，支持的想法，GJIC是必不可少的维持稳态。
A growing body of evidence from in vitro studies indicates that gap junction proteins connexins may have a tumor-suppressor function. Our previous double transfection experiments on HeLa cells have shown that a dominant-negative mutant V139 M of connexin32 (Cx32) can abolish gap junctional intercellular communication (GJIC). To examine whether the same dominant-negative mutant of Cx32 inhibits GJIC between hepatocytes in vivo and thus modulates cell proliferation and susceptibility to hepatocarcinogenesis, we created transgenic mice with the mutant Cx32 gene driven by a liver-specific albumin promoter. These mice developed normally both before and after birth, and GJIC in their liver was diminished, as expected. No increase in incidence of spontaneous tumors of any site was observed in the transgenic mice. Rather unexpectedly, cell proliferation during liver regeneration after partial hepatectomy was retarded by 24 h in the transgenic mice compared with the wild-type mice. In contrast, the transgenic male mice were more susceptible to diethylnitrosamine-induced hepatocarcinogenesis, developing more liver tumors with shorter latency. These results show that GJIC can coordinate cell growth both positively and negatively in vivo, supporting the idea that GJIC is essential for maintenance of homeostasis.