Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells.
Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells.
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发表时间：
1999-04
期刊：
影响因子：
11.2
通讯作者：
L. R. Howe;L. R. Howe;K. Subbaramaiah;K. Subbaramaiah;W. Chung;W. Chung;Andrew J. Dannenberg;Anthony M. C. Brown;Anthony M. C. Brown
中科院分区：
文献类型：
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作者：
L. R. Howe;L. R. Howe;K. Subbaramaiah;K. Subbaramaiah;W. Chung;W. Chung;Andrew J. Dannenberg;Anthony M. C. Brown;Anthony M. C. Brown
Wnt-1在小鼠乳腺异位表达时作为乳腺癌基因发挥作用。APC是一种肿瘤抑制基因，其突变导致人类和啮齿动物的肠道肿瘤发生。Wnt-1表达和APC突变都激活了一个共同的信号通路，涉及由β-连环蛋白/Tcf复合物介导的转录激活，但与致癌相关的靶点很少。诱导型前列腺素合酶环氧合酶-2的表达对于APC突变导致的肠道肿瘤发生至关重要，这表明环氧合酶-2可能是β-连环蛋白/Tcf复合物的转录靶点。在这里，我们研究了Wnt-1对环氧合酶-2表达的影响。Wnt-1在小鼠乳腺上皮细胞系RAC 311和C57 MG中的表达诱导胞浆β-连环蛋白的稳定和形态转化。Wnt-1在这些细胞中的表达引起环氧合酶-2基因的转录上调，导致环氧合酶-2 mRNA和蛋白水平的增加。前列腺素E2的产生增加的结果，环氧合酶-2活性升高，并可以减少治疗与选择性环氧合酶-2抑制剂。因此，环氧合酶-2似乎是APC突变和Wnt-1表达的常见下游靶标。鉴于环氧合酶-2在肠道肿瘤发生中的关键作用，环氧合酶-2对Wnt信号的响应上调可能有助于Wnt诱导的乳腺癌发生。
Wnt-1 acts as a mammary oncogene when ectopically expressed in the mouse mammary gland. APC is a tumor suppressor gene, mutations in which cause intestinal tumorigenesis in humans and rodents. Both Wnt-1 expression and APC mutation activate a common signaling pathway involving transcriptional activation mediated by beta-catenin/Tcf complexes, but few targets relevant to carcinogenesis have yet been identified. Expression of the inducible prostaglandin synthase cyclooxygenase-2 appears critical for intestinal tumorigenesis resulting from APC mutation, suggesting that cyclooxygenase-2 might be a transcriptional target for beta-catenin/Tcf complexes. Here, we have investigated the effect of Wnt-1 on cyclooxygenase-2 expression. Wnt-1 expression in the mouse mammary epithelial cell lines RAC311 and C57MG induces stabilization of cytosolic beta-catenin and morphological transformation. Expression of Wnt-1 in these cells caused transcriptional up-regulation of the cyclooxygenase-2 gene, resulting in increased levels of cyclooxygenase-2 mRNA and protein. Prostaglandin E2 production was increased as a consequence of the elevated cyclooxygenase-2 activity and could be decreased by treatment with a selective cyclooxygenase-2 inhibitor. Cyclooxygenase-2 thus appears to be a common downstream target for APC mutation and Wnt-1 expression. In view of the critical role of cyclooxygenase-2 in intestinal tumorigenesis, cyclooxygenase-2 up-regulation in response to Wnt signaling may contribute to Wnt-induced mammary carcinogenesis.