Gap junction genes Cx26 and Cx43 individually suppress the cancer phenotype of human mammary carcinoma cells and restore differentiation potential.
Gap junction genes Cx26 and Cx43 individually suppress the cancer phenotype of human mammary carcinoma cells and restore differentiation potential.
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发表时间：
1996-07
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通讯作者：
K. Hirschi;Cheng Xu;T. Tsukamoto;R. Sager
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作者：
K. Hirschi;Cheng Xu;T. Tsukamoto;R. Sager
正常人乳腺上皮细胞表达 hcx43 和 hCx26 蛋白，形成功能性间隙连接通道。两个 Cx 基因在乳腺癌细胞系中转录下调；因此，不会产生蛋白质并且不存在间隙连接。这一结果表明间隙连接通讯的丧失可能在致癌过程中发挥重要作用。为了解决这个问题，在人乳腺癌细胞（MDA-MB-435）的再克隆系中产生了两组稳定转染子。一组表达hCx26，另一组表达hCx43。对含有功能性间隙连接的转染子的研究表明，它们在培养物中比对照生长得更慢，并且它们的肿瘤形成能力被强烈抑制。在旨在检查其分化能力的研究中，发现这些转染子已恢复在基质胶基质中形成三维结构的能力。这种特性是正常乳腺上皮细胞的特征，但它在亲本肿瘤细胞和新转染子对照中丢失。因此，这里显示连接通讯在乳腺结构的形态发生中发挥决定性作用。 hCx26 和 hCx43 基因在培养物和动物试验中均表现为经典的肿瘤抑制基因，可恢复转移性乳腺癌细胞的生长调节特性。当转染细胞嵌入基质胶基质中时，这些基因的表达进一步诱导分化能力，如三维结构的形成所示。这些发现表明间隙连接的重新表达可能在肿瘤细胞行为正常化中发挥至关重要的作用。
Normal human mammary epithelial cells express hcx43 and hCx26 proteins, which form functional gap junction channels. Both Cx genes are transcriptionally down-regulated in mammary carcinoma cell lines; consequently, no protein is made and gap junctions are absent. This result suggests that the loss of gap junctional communication may play an important role in carcinogenesis. To address this question, two sets of stable transfectants were produced in a recloned line of human mammary carcinoma cells (MDA-MB-435). One set expressed hCx26, and the other expressed hCx43. Studies of transfectants that contain functional gap junctions showed that they grew more slowly in culture than controls, and that their tumor-forming ability was strongly suppressed. In studies designed to examine their differentiation capacity, these transfectants were found to have regained the capacity to form three-dimensional structures in a matrigel matrix. This property is characteristic of normal mammary epithelial cells, but it is lost in the parental tumor cells and neo-transfectant controls. Thus, junctional communication is shown here to play a decisive role in the morphogenesis of mammary gland structures. The hCx26 and hCx43 genes behave as classical tumor suppressor genes both in culture and in animal tests in restoring growth regulatory properties to metastatic mammary carcinoma cells. Expression of these genes further induces the ability to differentiate as shown by the formation of three-dimensional structures when transfected cells are embedded in a matrigel matrix. These findings suggest that the reexpression of gap junctions may play a vital role in normalizing tumor cell behavior.