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Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression


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 models3. 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.

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Figure 1: KAI1 interacts with DARC in vitro.
Figure 2: Interaction of KAI1 and DARC leads to growth arrest of cancer cells.
Figure 3: KAI1 does not suppress spontaneous lung metastasis in DARC knockout mice.

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This work was supported by the US Department of Defense (PC031038, BC044370), the National Institutes of Health (R15VS079473, 5R01CA89438-03 supplement), the McElroy Foundation, the American Lung Association of Illinois and the Illinois Department of Public Health.

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Correspondence to Kounosuke Watabe.

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Bandyopadhyay, S., Zhan, R., Chaudhuri, A. et al. Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nat Med 12, 933–938 (2006).

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