Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression
Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression
复制标题
DOI：
10.1038/nm1444
复制
发表时间：
2006-08-01
期刊：
影响因子：
82.9
通讯作者：
Watabe, Kounosuke
中科院分区：
文献类型：
--
作者：
Bandyopadhyay, Sucharita;Zhan, Rui;Watabe, Kounosuke
CD 82，也称为KAI 1，最近被鉴定为人染色体11p1.2上的前列腺癌转移抑制基因（参考文献1）。CD 82的产物是KAI 1，一种40- 75-kDa的四跨膜蛋白细胞表面蛋白，也称为白细胞表面标志物CD 82（参考文献104）。1、2）。已发现KAI 1的下调与多种癌症的转移进展临床相关，而CD 82的过表达在多种动物模型中特异性抑制肿瘤转移（3）。为了确定KAI 1的作用机制，我们使用酵母双杂交筛选并鉴定了内皮细胞表面蛋白DARC（也称为gp-Fy）作为KAI 1的相互作用伴侣。我们的研究结果表明，表达KAI 1的癌细胞通过KAI 1和DARC之间的直接相互作用附着于血管内皮细胞，并且这种相互作用通过调节TBX 2和p21的表达而导致肿瘤细胞增殖的抑制和衰老的诱导。此外，KAI 1的转移抑制活性在DARC敲除小鼠中显著受损，而KAI 1在野生型和杂合子同窝仔中完全消除肺转移。这些结果提供了直接的证据，DARC是必不可少的功能的CD 82作为一个抑制剂的转移。
CD82, also known as KAI1, was recently identified as a prostate cancer metastasis suppressor gene on human chromosome 11p1.2 (ref. 1). The product of CD82 is KAI1, a 40- to 75-kDa tetraspanin cell-surface protein also known as the leukocyte cell-surface marker CD82 (refs. 1,2). Downregulation of KAI1 has been found to be clinically associated with metastatic progression in a variety of cancers, whereas overexpression of CD82 specifically suppresses tumor metastasis in various animal models(3). To define the mechanism of action of KAI1, we used a yeast two-hybrid screen and identified an endothelial cell-surface protein, DARC (also known as gp-Fy), as an interacting partner of KAI1. Our results indicate that the cancer cells expressing KAI1 attach to vascular endothelial cells through direct interaction between KAI1 and DARC, and that this interaction leads to inhibition of tumor cell proliferation and induction of senescence by modulating the expression of TBX2 and p21. Furthermore, the metastasis-suppression activity of KAI1 was significantly compromised in DARC knockout mice, whereas KAI1 completely abrogated pulmonary metastasis in wild-type and heterozygous littermates. These results provide direct evidence that DARC is essential for the function of CD82 as a suppressor of metastasis.