MUC1 Protein Expression in Tumor Cells Regulates Transcription of Proinflammatory Cytokines by Forming a Complex with Nuclear Factor-κB p65 and Binding to Cytokine Promoters IMPORTANCE OF EXTRACELLULAR DOMAIN
MUC1 Protein Expression in Tumor Cells Regulates Transcription of Proinflammatory Cytokines by Forming a Complex with Nuclear Factor-κB p65 and Binding to Cytokine Promoters IMPORTANCE OF EXTRACELLULAR DOMAIN
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DOI：
10.1074/jbc.m111.297630
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发表时间：
2011-12-09
影响因子：
4.8
通讯作者：
Finn, Olivera J.
中科院分区：
文献类型：
--
作者：
Cascio, Sandra;Zhang, Lixin;Finn, Olivera J.
MUC 1是一种跨膜糖蛋白，在人类腺癌的所有发展阶段都异常表达。与正常上皮细胞相比，MUC 1在癌细胞中的过表达和低糖基化可能改变其功能并影响癌细胞的行为。细胞外结构域，特别是高度O-糖基化的VNTR（可变数目的串联重复序列）区域，在细胞间通讯中起着重要的作用，然而，我们在这里表明，它也参与细胞内NF-κ B通路的激活。用编码具有22个串联重复序列（MUC 1/22 TR）或两个串联重复序列（MUC 1/2 TR）或两个缺乏VNTR区域的同种型（MUC 1/Z和MUC 1/Y）的MUC 1的cDNA转染MUC 1（-）肿瘤细胞，显示NF-κ B家族成员的最高表达水平与VNTR的存在和最高数量的串联重复序列相关。由于MUC 1与VNTR在肿瘤上的表达先前与先天免疫系统细胞的趋化活性相关，我们研究了MUC 1表达对促炎细胞因子的NF-κ B依赖性转录调节的影响。ChIP和实时PCR实验显示，MUC 1/22 TR通过以NF-κ B p65依赖性方式与表达内源性MUC 1的MUC 1转染的人乳腺癌细胞和人乳腺癌细胞的启动子区结合，上调IL-6和TNF-α的表达。这种新发现的MUC 1和p65复合物是肿瘤可用于促进炎症和癌症发展的新机制。
MUC1 is a transmembrane glycoprotein abnormally expressed in all stages of development of human adenocarcinomas. Overexpression and hypoglycosylation of MUC1 in cancer cells compared with normal epithelial cells are likely to alter its function and affect the behavior of cancer cells. The extracellular domain, specifically the highly O-glycosylated VNTR (variable number of tandem repeats) region, plays an important role in cell-cell communication; however, we show here that it also participates intracellularly in activation of the NF-kappa B pathway. Transfection of MUC1(-) tumor cells with cDNA encoding MUC1 with 22 tandem repeats (MUC1/22TR) or two tandem repeats (MUC1/2TR) or two isoforms that lack the VNTR region (MUC1/Z and MUC1/Y) showed that the highest expression levels of NF-kappa B family members correlated with the presence of VNTR and the highest number of tandem repeats. Because expression of MUC1 with VNTR on tumors was previously associated with chemotactic activity for cells of the innate immune system, we investigated the influence of MUC1 expression on the NF-kappa B-dependent transcriptional regulation of proinflammatory cytokines. ChIP and real-time PCR experiments revealed that MUC1/22TR up-regulated IL-6 and TNF-alpha expression by binding to their promoter regions in a NF-kappa B p65-dependent manner in both MUC1-transfected and human breast cancer cells that express endogenous MUC1. This newly detected complex of MUC1 and p65 is a novel mechanism that tumors can use to promote inflammation and cancer development.