Research for Mechanism of Connexin Dysfunction during Carcinogenesis of Edometrium

有几条证据表明，连接蛋白表达在几个器官的癌前病变中被抑制和/或异常定位，并且许多（如果不是全部的话）肿瘤促进剂已显示出抑制培养细胞以及体内细胞的间隙连接细胞间通讯（GJIC），这表明GJIC的丧失增强克隆分散，导致来自周围细胞的生长抑制信号丢失。对于子宫内膜癌的发生，可以得出结论，GJIC的表达抑制和连接蛋白的异常定位所造成的损失支持子宫内膜癌细胞起源于增生细胞的克隆性进化。在本研究中，过表达ER-α的IK-ER 1的GJIC在含有雌二醇的培养基中显著降低，并且发现这种降低被ICI 182. 780（一种纯抗雌激素底物）抑制，如荧光素黄染料转移试验所证明的。蛋白质印迹分析表明， ...更多信息 艾德发现E（+）组Cx 26和Cx 32表达均降低，而ICI182.780可抑制这种降低。这些结果支持染料转移测定的结果。因此，雌激素抑制子宫内膜上皮细胞连接蛋白的表达，导致细胞增殖，可能是子宫内膜的促肿瘤剂。它包括将能够将无毒前药转化为细胞毒性药物的基因导入癌细胞。由于这种治疗基因不能轻易地引入肿瘤的整个细胞群，因此肿瘤的成功根除取决于一种称为“旁观者效应”的现象，通过这种现象，引入的基因甚至可以影响其本身不存在的细胞。从治疗的角度来看，通过各种手段增强这种现象以实现肿瘤根除可能至关重要。一种这样的自杀基因，来自单纯疱疹病毒的胸苷激酶基因，与前药更昔洛韦组合，已被广泛和成功地用于一些动物模型，表现出强烈的旁观者效应。在参与该现象的机制中，GJIC直接参与更昔洛韦的毒性代谢物的转移，其直接从单纯疱疹病毒胸苷激酶表达细胞传递到不表达其的周围细胞。因为GJIC似乎是体外和体内旁观者效应的介导者，在这里，我们回顾了通过增加肿瘤内GJIC能力来提高肿瘤细胞死亡程度的可能的分子策略。少

There are several lines of evidence suggesting that connexin expression is suppressed and/or aberrantly localized in pre-cancerous lesions in several organs and many, if not all, tumor-promoting agents have been shown to inhibit gap junctional intercellular communication (GJIC) of cultured cells as well as those in vivo, suggesting that the loss of GJIC enhances clonal dispersion, causing loss of the growth-suppression signals from the surrounding cells. For endometrial carcinogenesis, it may be concluded that the loss of GJIC caused by the suppressed expression and the aberrant localization of connexin support the clonal evolution of endometrial cancer cells originating in the hyperplasia cells. In the present study, GJIC of IK-ER1, which overexpresses ER-α, was markedly reduced in the estradiol-containing medium and the reduction was found to be inhibited by ICI182.780, a pure anti-estrogen substrate, as demonstrated by Lucifer-Yellow dye-transfer assay. Western blot analysis indicat … More ed that the expression of both Cx26 and Cx32 also decreased in E(+) and the reduction was inhibited by adding ICI182.780. These results supported the result of the dye-transfer assay. Thus, estrogen, which suppresses connexin expression of endometrial epithelium and causes cell proliferation, may act as a tumor-promoting agent for endometrium.Antitumor suicide gene therapy is one of the emerging strategies against cancer. It consists of the introduction into cancer cells of a gene capable of converting a nontoxic prodrug into a cytotoxic drug. Because this therapeutic gene cannot be easily introduced into the whole cell population of a tumor, the successful eradication of tumors depends on a phenomenon called the "bystander effect," by which the introduced gene can affect even cells in which it is not itself present. From a therapeutic point of view, it may be crucial to enhance this phenomenon through various means to achieve tumor eradication. One such suicide gene, the thymidine kinase gene from the herpes simplex virus, in combination with the prodrug ganciclovir, has been extensively and successfully used in some animal models exhibiting a strong bystander effect. Among the mechanisms involved in this phenomenon GJIC is directly involved in the transfer of the toxic metabolites of ganciclovir, which pass directly from herpes simplex virus thymidine kinase-expressing cells to surrounding cells that do not express it. Because GJIC appears to be a mediator of the bystander effect both in vitro and in vivo, here we review possible molecular strategies for enhancing the extent of tumor cell death by increasing the intratumoral GJIC capacity. Less