Research for Mechanism of Connexin Dysfunction during Carcinogenesis of Edometrium

有多条证据表明，连接蛋白的表达受到抑制和/或异常定位于癌前病变的多个器官，许多(如果不是全部)促癌剂已被证明抑制培养细胞和体内细胞的缝隙连接细胞间通讯(GJIC)，表明GJIC的丢失加强了克隆分散，导致周围细胞生长抑制信号的丢失。在子宫内膜癌变过程中，连接蛋白表达受抑所致的GJIC缺失和定位异常可能支持子宫内膜癌细胞起源于增生性细胞的克隆性进化。在本研究中，高表达ER-α的IK-ER1细胞的GJIC在含雌二醇的介质中显著降低，并被一种纯的抗雌激素底物ICI182.780抑制。蛋白质印迹分析指示…进一步研究发现，Cx26和Cx32在E(+)细胞中的表达也降低，加入ICI182.780可抑制这种降低。这些结果支持染料转移试验的结果。因此，雌激素抑制子宫内膜上皮细胞连接蛋白的表达，促进细胞增殖，可能是子宫内膜的促癌剂。抗肿瘤自杀基因治疗是新兴的抗癌策略之一。它包括将一种基因导入癌细胞，该基因能够将无毒的前药转化为细胞毒药物。由于这种治疗性基因不能轻易地导入到肿瘤的整个细胞群体中，因此肿瘤的成功根除依赖于一种被称为“旁观者效应”的现象，通过这种现象，被引入的基因甚至可以影响到它本身并不存在的细胞。从治疗的角度来看，通过各种手段加强这种现象以实现肿瘤根除可能是至关重要的。其中一种自杀基因，来自单纯疱疹病毒的胸苷激酶基因，与前药更昔洛韦相结合，已被广泛并成功地应用于一些表现出强烈旁观者效应的动物模型中。在这一现象涉及的机制中，GJIC直接参与了更昔洛韦的毒性代谢产物的转移，这些代谢产物直接从表达单纯疱疹病毒胸苷激酶的细胞传递到不表达它的周围细胞。由于GJIC在体外和体内似乎都是旁观者效应的媒介，因此我们在这里综述了通过增加GJIC的瘤内容量来提高肿瘤细胞死亡程度的可能的分子策略。较少

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