Rat MUC4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for Herceptin resistance
Rat MUC4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for Herceptin resistance
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DOI：
10.1002/ijc.10410
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发表时间：
2002-06-20
影响因子：
6.4
通讯作者：
Carraway, KL
中科院分区：
文献类型：
--
作者：
Price-Schiavi, SA;Jepson, S;Carraway, KL
Muc4（也称为唾液黏液蛋白复合物）是一种异二聚体糖蛋白复合物，它与人Muc4的大鼠同源物，由外周o糖基化的黏液蛋白亚基ASGP-1组成，与n糖基化的跨膜亚基ASGP-2紧密但非共价连接。该复合物在许多正常、易损的上皮组织中表达，包括乳腺、子宫、结肠、角膜和气管。Muc4/ SMC在包括乳腺肿瘤在内的许多人类肿瘤中也过表达或异常表达。Muc4/SMC的过表达已被证明可以阻断细胞间和细胞基质间的相互作用，保护肿瘤细胞免受免疫监视并促进转移。此外，作为ErbB2的配体，Muc4/SMC可以增强ErbB2的磷酸化，并可能改变该受体产生的信号。利用稳定转染四环素可调节Muc4的A375人黑色素瘤细胞和MCF7人乳腺腺癌细胞，我们研究了Muc4/SMC过表达是否可以抑制抗体与细胞表面表达的ErbB2的结合。Muc4/SMC的过表达不影响ErbB2在两种细胞系中的表达水平，但它确实降低了一些抗ErbB2抗体的结合，包括赫赛汀。有趣的是，ErbB2的过表达不会阻断其他不相关的相同同型抗体的结合，这表明ErbB2抗体结合的减少是由于Muc4/SMC和ErbB2复合物的形成。此外，Muc4/SMC上的抗Muc4/SMC抗体减少了抗体与ErbB2的结合，而不是增加了抗体与ErbB2的结合，这再次表明，抗体与ErbB2结合减少是由于Muc4/SMC和ErbB2复合物形成的空间位阻。因此，Muc4/SMC在肿瘤细胞上的过表达可能具有预后和治疗相关性。(C) 2002 Wiley-Liss, Inc。
Muc4 (also called sialomucin complex), the rat homolog of human MUC4, is a heterodimeric glycoprotein complex that consists of a peripheral O-glycosylated mucin subunit, ASGP-1, tightly but noncovalently linked to a N-glycosylated transmembrane subunit, ASGP-2. The complex is expressed in a number of normal, vulnerable epithelial tissues, including mammary gland, uterus, colon, cornea and trachea. Muc4/ SMC is also overexpressed or aberrantly expressed on a number of human tumors including breast tumors. Overexpression of Muc4/SMC has been shown to block cell-cell and cell-matrix interactions, protect tumor cells from immune surveillance and promote metastasis. In addition, as a ligand for ErbB2, Muc4/SMC can potentiate phosphorylation of ErbB2 and potentially alter signals generated from this receptor. Using A375 human melanoma cells and MCF7 human breast adenocarcinoma cells stably transfected with tetracycline regulatable Muc4, we have investigated whether overexpression of Muc4/SMC can repress antibody binding to cell surface-expressed ErbB2. Overexpression of Muc4/SMC does not affect the level of ErbB2 expression in either cell line, but it does reduce binding of a number of anti-ErbB2 antibodies, including Herceptin. Interestingly, overexpression of ErbB2 does not block binding of other unrelated antibodies of the same isotype, suggesting that the reduction in ErbB2 antibody binding is due to complex formation of Muc4/SMC and ErbB2. Furthermore, capping of Muc4/SMC with anti-Muc4/ SMC antibodies reduces antibody binding to ErbB2 instead of increasing binding, again suggesting that reduced antibody binding to ErbB2 is due to steric hindrance from complex formation of Muc4/SMC and ErbB2. Thus, overexpression of Muc4/SMC on tumor cells may have both prognostic and therapeutic relevance. (C) 2002 Wiley-Liss, Inc.