Inhibition of MUC1 expression by indole-3-carbinol.
Inhibition of MUC1 expression by indole-3-carbinol.
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Indole-3-carbinol 对 MUC1 表达的抑制。
DOI：
10.1002/ijc.20031
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发表时间：
2004
影响因子：
6.4
通讯作者：
Kim,KwangChul
中科院分区：
文献类型：
--
作者：
Lee,InsongJ;Han,Feng;Baek,Jin;Hisatsune,Akinori;Kim,KwangChul
MUC1是一种大的跨膜糖蛋白，在大多数肿瘤中过度表达。MUC1的高表达与侵袭性肿瘤有关，MUC1抗原被用作监测乳腺癌患者疾病进展的标志物。一些证据有力地表明，MUC1的过度表达有助于癌症的进展和转移。在这份报告中，我们证明了自然产生的癌症预防药物吲哚-3-甲醇(I3C)可以抑制乳腺癌细胞中MUC1的表达。I3C以剂量和时间依赖的方式抑制MUC1mRNA和蛋白水平。这种抑制作用存在于雌激素敏感的MCF-7细胞和不敏感的MDA-MB-468细胞中，表明该抑制通路不依赖于雌激素受体。利用人MUC1基因启动子连接到荧光素酶报告基因的基因表达研究表明，I3C抑制MUC1基因的转录。启动子缺失研究表明，启动子起始点上游600bp(−600)的区域足以被I3C抑制。此外，I3C还抑制了−600和−450bp之间区域介导的转录激活。一个可能的异源反应元件位于该区域内，但通过凝胶迁移率改变分析无法检测到AhR/Arnt异源二聚体与该区域的结合。我们的结果可能表明I3C在癌细胞中存在一种新的转录抑制途径以及一种新的MUC1基因抑制机制。我们的发现可能对I3C作为乳腺癌的预防和治疗药物的使用具有一定的指导意义。©2004 Wiley-Liss Inc.
MUC1 is a large transmembrane glycoprotein overexpressed by a majority of carcinomas. High expression of MUC1 is associated with aggressive tumors, and MUC1 antigen is used as a marker to monitor disease progression in breast cancer patients. Several lines of evidence strongly suggest that the overexpression of MUC1 contributes to cancer progression and metastasis. In this report, we demonstrate that the naturally occurring cancer preventative, indole‐3‐carbinol (I3C), inhibits the expression of MUC1 in breast cancer cells. I3C inhibited both MUC1 mRNA and protein levels in a dose‐ and time‐dependent manner. This inhibition was seen in the estrogen responsive MCF‐7 cells as well as unresponsive MDA‐MB‐468 cells, indicating that the inhibitory pathway is independent of estrogen receptor. Gene expression studies using the humanMUC1gene promoter connected to a luciferase reporter demonstrated that I3C inhibits the transcription of theMUC1gene. Promoter deletion studies indicate that the region containing up to 600 bp upstream (−600) of the initiation site is sufficient for inhibition by I3C. Furthermore, I3C represses the activation of transcription mediated by the region between −600 and −450 bp. A putative xenobiotic response element was located within this region but the binding of AhR/Arnt heterodimer to this site was undetectable by electrophoretic mobility shift assays. Our results may point to the existence of a novel pathway of transcriptional inhibition by I3C in cancer cells as well as a new mechanism ofMUC1gene inhibition. Our findings might have implications in the use of I3C as a preventative as well as a therapeutic agent for breast cancer. © 2004 Wiley‐Liss, Inc.