Lin Kwang-Huei, Wang Won-Jing, Wu Yi-Hsin, Cheng Sheue-Yann
Department of Biochemistry, Chang-Gung University, Taoyuan, Taiwan, Republic of China.
Endocrinology. 2002 Feb;143(2):467-75. doi: 10.1210/endo.143.2.8620.
Metastasis of various malignant cells is inversely related to the abundance of the Nm23-H1 protein. The role of estrogens in tumor metastasis has now been investigated by examining the effect of E2 on the expression of the Nm23-H1 gene. Three human breast carcinoma cell lines, in which endogenous ERalpha is expressed at different levels, were used as a tool to assess the role of ERalpha in Nm23-H1 gene-mediated metastasis. E2 induced time-dependent increases in the abundance of Nm23-H1 mRNA and protein, with the extent of these effects correlating with the level of expression of ERalpha. E2 induced a marked decrease in the invasive activity of MCF-7 and BT-474 cells but had no effect on BCM-1 cells, which had virtually no ERalpha. Consistent with these results, the ER-mediated Nm23-H1 promoter activity was inhibited 3-fold by the E2 antagonist, ICI 182,780. Deletion analysis of the promoter region of the Nm23-H1 gene identified a positive estrogen-responsive element located in -108/-94. ER protein bound specifically to the -108/-79 fragment with high avidity. These results indicate that E2, acting through ERalpha, activated transcription of the Nm23-H1 gene via a positive estrogen-responsive element in the promoter region of the gene. These results suggest that E2 could suppress tumor metastasis by activating the expression of the Nm23-H1 gene.
多种恶性细胞的转移与Nm23-H1蛋白的丰度呈负相关。现在通过检测E2对Nm23-H1基因表达的影响来研究雌激素在肿瘤转移中的作用。使用三种内源性ERα表达水平不同的人乳腺癌细胞系作为评估ERα在Nm23-H1基因介导的转移中作用的工具。E2诱导Nm23-H1 mRNA和蛋白丰度随时间增加，这些效应的程度与ERα的表达水平相关。E2显著降低了MCF-7和BT-474细胞的侵袭活性，但对几乎没有ERα的BCM-1细胞没有影响。与这些结果一致，E2拮抗剂ICI 182,780将ER介导的Nm23-H1启动子活性抑制了3倍。对Nm23-H1基因启动子区域的缺失分析确定了位于-108/-94的一个阳性雌激素反应元件。ER蛋白以高亲和力特异性结合到-108/-79片段。这些结果表明，E2通过ERα起作用，通过基因启动子区域的一个阳性雌激素反应元件激活Nm23-H1基因的转录。这些结果表明，E2可通过激活Nm23-H1基因的表达来抑制肿瘤转移。
