Both early and late stages of hepatocarcinogenesis are enhanced in cx32 dominant negative mutant transgenic rats with disrupted gap junctional intercellular communication
Both early and late stages of hepatocarcinogenesis are enhanced in cx32 dominant negative mutant transgenic rats with disrupted gap junctional intercellular communication
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DOI：
10.1007/s00232-007-9053-9
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发表时间：
2007-08-01
影响因子：
2.4
通讯作者：
Shirai, Tomoyuki
中科院分区：
文献类型：
--
作者：
Hokaiwado, Naomi;Asamoto, Makoto;Shirai, Tomoyuki
连接蛋白是一个跨膜蛋白家族，在介导细胞间通讯的差距连接中起重要作用。据报道，几个连接蛋白是肿瘤抑制因子，我们已经建立了一个连接蛋白32（Cx 32）显性负突变的转基因（Tg）大鼠表现出高敏感性的早期二乙基亚硝胺（DEN）诱导的肝癌。在这项研究中，我们进行了两个独立的实验，使用Tg大鼠，以进一步研究破坏Cx 32在晚期肝癌（癌诱导和转移）在肝脏中的作用。在第一个实验中，为期50周，在6周龄和26周龄时给予DEN，以探索致癌物治疗在不同阶段的影响。与非Tg大鼠相比，Tg大鼠肝细胞癌（HCC）的数量显著增加。第二个实验集中于Cx 32破坏对由DEN和N-亚硝基吗啉给药诱导的HCC转移的影响。只有Tg大鼠在肺中具有多个HCC转移，并且与非Tg大鼠相比，Tg大鼠中HCC的发育和生长显著加速。因此，Cx 32的正常功能可能是抑制肝癌发生的早期和晚期阶段所必需的。
Connexins are a family of transmembrane proteins essential for the gap junctions, which mediate cell-to-cell communication. Several connexins are reported to be tumor suppressors, and we have established transgenic (Tg) rats with a connexin 32 (Cx32) dominant negative mutant showing high sensitivity to early-stage diethylnitrosamine (DEN)-induced liver carcinogenesis. In this study, we carried out two independent experiments using Tg rats to further investigate the roles of disrupted Cx32 in late-stage carcinogenesis (carcinoma induction and metastasis) in the liver. In the first experiment, of 50 weeks' duration, DEN was administered at 6 weeks of age and at 26 weeks to explore the effects of carcinogen treatments at different stages. The number of hepatocellular carcinomas (HCCs) was significantly increased in Tg compared with non-Tg rats. The second experiment focused on the effects of Cx32 disruption on metastasis by HCCs induced by administration of DEN and N-nitrosomorpholine. Only Tg rats had multiple metastases of HCCs in the lung, and the development and growth of HCCs was dramatically accelerated in Tg compared to non-Tg rats. Thus, normal function of Cx32 may be essential for suppression of both early and late stages of hepatocarcinogenesis.