Induction of the LRP16 gene by estrogen promotes the invasive growth of Ishikawa human endometrial cancer cells through the downregulation of E-cadherin
Induction of the LRP16 gene by estrogen promotes the invasive growth of Ishikawa human endometrial cancer cells through the downregulation of E-cadherin
复制标题
雌激素诱导LRP16基因通过下调E-钙粘蛋白促进石川人子宫内膜癌细胞的侵袭性生长
DOI：
10.1038/cr.2007.79
复制
发表时间：
2007-10-01
期刊：
影响因子：
44.1
通讯作者：
Mu, Yi Ming
中科院分区：
文献类型：
--
作者：
Meng, Yuan Guang;Han, Wei Dong;Mu, Yi Ming
LRP 16先前被鉴定为乳腺癌细胞中的雌激素诱导基因。LRP 16对雌激素的反应性及其在子宫内膜癌（EC）细胞中的功能作用尚不清楚。在此，我们发现，在雌激素受体α（ER α）阳性的石川人EC细胞中，17 β-雌二醇（E2）显著增加了LRP 16基因的mRNA水平和启动子活性。虽然LRP 16的异位表达对石川细胞的生长速率没有明显影响，但Transwell测定的结果显示，LRP 16过表达细胞的侵袭能力增加了约三分之一。作为分子筛选的结果，我们观察到E-cadherin（一种与肿瘤转移相关的重要粘附分子）的表达被LRP 16抑制。进一步的启动子分析表明LRP 16以剂量依赖性方式抑制E-钙粘蛋白的反式激活。然而，这种抑制作用被雌激素剥夺所消除，表明LRP 16下调E-cadherin转录需要ER α介导。染色质免疫沉淀分析显示，ER α与E-cadherin启动子的结合被LRP 16拮抗，表明LRP 16可以干扰ER α介导的转录。这些结果表明，LRP 16的上调雌激素可能参与了在人类EC的侵袭性生长下调E-钙粘蛋白。
LRP16 was previously identified as an estrogen-induced gene in breast cancer cells. The responsiveness of LRP16 to estrogen and its functional effects in endometrial cancer (EC) cells are still unclear. Here, we show that the mRNA level and promoter activity of the LRP16 gene were significantly increased by 17β-estradiol (E2) in estrogen receptor α (ERα)-positive Ishikawa human EC cells. Although the growth rate of Ishikawa cells was not obviously affected by ectopic expression of LRP16, the results of a Transwell assay showed an approximate one-third increase of the invasive capacity of LRP16-overexpressing cells. As a result of molecular screening, we observed that the expression of E-cadherin, an essential adhesion molecule associated with tumor metastasis, was repressed by LRP16. Further promoter analyses demonstrated that LRP16 inhibited E-cadherin transactivation in a dose-dependent manner. However, the inhibition was abolished by estrogen deprivation, indicating that the downregulation of E-cadherin transcription by LRP16 requires ERα mediation. Chromatin immunoprecipitation analyses revealed that the binding of ERα to the E-cadherin promoter was antagonized by LRP16, suggesting that LRP16 could interfere with ERα-mediated transcription. These results suggest that the upregulation of LRP16 by estrogen could be involved in invasive growth by downregulating E-cadherin in human ECs.