Bandyopadhyay Sucharita, Zhan Rui, Chaudhuri Asok, Watabe Misako, Pai Sudha K, Hirota Shigeru, Hosobe Sadahiro, Tsukada Taisei, Miura Kunio, Takano Yukio, Saito Ken, Pauza Mary E, Hayashi Sunao, Wang Ying, Mohinta Sonia, Mashimo Tomoyuki, Iiizumi Megumi, Furuta Eiji, Watabe Kounosuke
Southern Illinois University School of Medicine, Department of Medical Microbiology, Immunology and Cell Biology, 801 N. Rutledge Street, PO Box 19626, Springfield, Illinois 62794-9626, USA.
Nat Med. 2006 Aug;12(8):933-8. doi: 10.1038/nm1444. Epub 2006 Jul 23.
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. 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.
CD82，也被称为KAI1，最近被确定为人类染色体11p1.2上的前列腺癌转移抑制基因（参考文献1）。CD82的产物是KAI1，一种40至75千道尔顿的四跨膜蛋白，位于细胞表面，也被称为白细胞细胞表面标志物CD82（参考文献1、2）。已发现KAI1的下调在临床上与多种癌症的转移进展相关，而CD82的过表达在各种动物模型中能特异性抑制肿瘤转移。为了确定KAI1的作用机制，我们利用酵母双杂交筛选并鉴定出一种内皮细胞表面蛋白DARC（也称为gp-Fy）作为KAI1的相互作用蛋白。我们的结果表明，表达KAI1的癌细胞通过KAI1与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TBX2和p21的表达导致肿瘤细胞增殖受到抑制并诱导衰老。此外，在DARC基因敲除小鼠中，KAI1的转移抑制活性显著受损，而在野生型和杂合子同窝小鼠中，KAI1完全消除了肺转移。这些结果提供了直接证据，表明DARC对于CD82作为转移抑制因子的功能至关重要。
