Alternative titles; symbols
HGNC Approved Gene Symbol: CD82
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38): 11:44,564,409-44,620,358 (from NCBI)
Ichikawa et al. (1991) demonstrated by somatic cell hybridization of highly metastatic and nonmetastatic rat prostate cancer cells that the resultant hybrids were nonmetastatic if all of the parental chromosomes were retained. Somatic hybrid segregants that underwent nonrandom chromosomal loss reexpressed high metastatic ability. These results demonstrated the existence of gene(s), the expression of which can suppress metastatic ability of prostate cancer cells. To identify the location of homologous gene(s) in the human, Ichikawa et al. (1992) introduced specific human chromosomes into highly metastatic rat prostatic cells by use of microcell-mediated chromosome transfer. Introduction of human chromosome 11 resulted in suppression of metastatic ability without suppression of the in vivo growth rate or tumorigenicity of the hybrid cells. Spontaneous deletion of portions of human chromosome 11 in some of the clones delineated the minimal portion of human chromosome 11 capable of suppressing prostate cancer metastases: 11p13-p11.2, not including the Wilms tumor-1 locus (607102).
Dong et al. (1995) isolated the metastasis suppressor gene on 11p11.2 by PCR methods and designated it KAI1 for 'kang ai' (Chinese for anticancer). Expression of this gene was reduced in human cell lines derived from metastatic prostate tumors. KAI1 specifies a protein of 267 amino acids, with 4 hydrophobic and presumably transmembrane domains and 1 large extracellular hydrophilic domain with 3 potential N-glycosylation sites. KAI1 is evolutionarily conserved, is expressed in many human tissues, and encodes a member of a structurally distinct family of leukocyte surface glycoproteins. Decreased expression of this gene may be involved in the malignant progression of prostate and other cancers. The gene has also been referred to as ST6. Sequence comparisons showed that KAI1 is likely the human homolog of the mouse leukocyte surface antigen R2, which in turn is similar to CD37 (151523) and CD53 (151525). It appears to be upregulated in activated T cells, i.e., it is an 'activation antigen' of T cells.
Guo et al. (1998) analyzed KAI1 mRNA expression in normal liver and in metastatic and nonmetastatic hepatocellular carcinoma (HCC) cells. Significantly lower KAI1 mRNA levels were found in metastatic HCC cells. Miyazaki et al. (2000) demonstrated immunohistochemically that the expression of KAI1 protein appears to be correlated with lymph node metastasis in esophageal squamous cell carcinoma (ESCC). None of 22 patients studied with ESCC showed mutation of the KAI1 gene by PCR-SSCP.
As noted, KAI1 is capable of inhibiting the metastatic process in experimental animals. The expression of the KAI1 gene is also downregulated during tumor progression of prostate, breast, lung, bladder, and pancreatic cancers in humans, and this downregulation appears to be at the level of transcription or posttranscription. Mashimo et al. (1998) found that the tumor suppressor gene p53 (TP53; 191170) can directly activate the KAI1 gene by interacting with the 5-prime upstream region. The p53 responding region is located approximately 860 bases upstream of the transcriptional initiation site, and contains a typical tandem repeat of the p53 consensus binding sequence. Mutations of this sequence abolish the responsiveness to p53 and also the ability to bind to p53 protein. Immunohistochemical analysis of 177 samples of human prostate tumors showed that the expression of the KAI1 gene correlated strongly with that of the p53 gene and that the loss of these 2 markers resulted in poor survival of patients. The data indicated a direct relationship between p53 and KAI1 genes and suggested that the loss of p53 function, which is commonly observed in many types of cancer, leads to downregulation of the KAI1 gene, which may result in progression of metastases.
Baek et al. (2002) demonstrated that interleukin-1-beta (IL1B; 147720) causes nuclear export of a specific NCOR (600849) corepressor complex, resulting in derepression of a specific subset of nuclear factor-kappa-B (NFKB; see 164011)-regulated genes. These genes are exemplified by the tetraspanin KAI1, which regulates membrane receptor function. Nuclear export of the NCOR/TAB2 (605101)/HDAC3 (605166) complex by IL1B is temporally linked to selective recruitment of a TIP60 (601409) coactivator complex. KAI1 is also directly activated by a ternary complex, dependent on the acetyltransferase activity of TIP60, that consists of the presenilin-dependent C-terminal cleavage product of the beta amyloid precursor protein (APP; 104760), FE65 (602709), and TIP60, identifying a specific in vivo gene target of an APP-dependent transcription complex in the brain.
Kim et al. (2005) reported that the downregulation of the metastasis suppressor gene KAI1 in prostate cancer cells involves the inhibitory actions of beta-catenin (116806), along with a reptin (TIP48; 604788) chromatin remodeling complex. This inhibitory function of beta-catenin-reptin requires both increased beta-catenin expression and recruitment of histone deacetylase activity. The coordinated actions of beta-catenin-reptin components that mediate the repressive state serve to antagonize a TIP60 coactivator complex that is required for activation; the balance of these opposing complexes controls the expression of KAI1 and metastatic potential. The molecular mechanisms underlying the antagonistic regulation of beta-catenin-reptin and the TIP60 coactivator complexes for the metastasis suppressor gene, KAI1, are likely to be prototypic of a selective downregulation strategy for many genes, including a subset of NF-kappa-B (see 164011) target genes.
Using a cell invasion assays, Jee et al. (2006) found CD82 overexpression reduced the invasiveness of a human nonsmall cell lung carcinoma cell line. RT-PCR and Western blot analyses showed elevated MMP9 (120361) mRNA and protein; however, gel zymography revealed reduced MMP9 enzymatic activity that could be attributed to elevated TIMP1 (305370) levels. Jee et al. (2006) concluded that CD82 overexpression can suppress tumor invasiveness and metastatic potential by inducing MMP9 inactivation via upregulation of TIMP1.
Using a yeast 2-hybrid screen, Bandyopadhyay et al. (2006) identified an endothelial cell-surface protein, DARC (613665), as an interacting partner of KAI1. They demonstrated that cancer cells expressing KAI1 attach to vascular endothelial cells through direct interaction between KAI1 and DARC, leading to inhibition of tumor cell proliferation and induction of senescence by modulating the expression of TBX2 (600747) and CDKN1A (116899). In DARC knockout mice, the metastasis-suppression activity of KAI1 was significantly compromised, whereas KAI1 completely abrogated pulmonary metastasis in wildtype and heterozygous littermates. Bandyopadhyay et al. (2006) concluded that DARC is essential for the function of KAI1 as a suppressor of metastasis.
GP78 (AMFR; 603243) is an E3 ubiquitin ligase that is integral to endoplasmic reticulum-associated degradation of diverse substrates. Tsai et al. (2007) found that GP78 had a causal role in metastasis of an aggressive human sarcoma and that its prometastatic activity required its E3 activity. Furthermore, GP78 associated with and targeted KAI1 for degradation. Suppression of GP78 increased KAI1 abundance and reduced the metastatic potential of tumor cells, an effect that was largely blocked by concomitant suppression of KAI1. Tsai et al. (2007) confirmed an inverse relationship between GP78 and KAI1 in human sarcoma tissue by microarray analysis.
Dong et al. (1997) reported that the KAI1 gene is contained within 80 kb of DNA. They identified 10 exons; however, 800 nucleotides of the 3-prime untranslated region were not characterized. Among KAI1 and several other members of the 'transmembrane 4 superfamily,' the locations of the splice sites relative to the structural domains of the encoded protein are conserved.
By study of human/rodent somatic cell hybrids, Virtaneva et al. (1993) demonstrated that the R2 gene (CD82) is located on 11p12.
Baek, S. H., Ohgi, K. A., Rose, D. W., Koo, E. H., Glass, C. K., Rosenfeld, M. G. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappa-B and beta-amyloid precursor protein. Cell 110: 55-67, 2002. [PubMed: 12150997] [Full Text: https://doi.org/10.1016/s0092-8674(02)00809-7]
Bandyopadhyay, S., Zhan, R., Chaudhuri, A., Watabe, M., Pai, S. K., Hirota, S., Hosobe, S., Tsukara, T., Miura, K., Takano, Y., Saito, K., Pauza, M. E., Hayashi, S., Wang, Y., Mohinta, S., Mashimo, T., Iiizumi, M., Furuta, E., Watabe, K. Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nature Med. 12: 933-938, 2006. [PubMed: 16862154] [Full Text: https://doi.org/10.1038/nm1444]
Dong, J.-T., Isaacs, W. B., Barrett, J. C., Isaacs, J. T. Genomic organization of the human KAI1 metastasis-suppressor gene. Genomics 41: 25-32, 1997. [PubMed: 9126478] [Full Text: https://doi.org/10.1006/geno.1997.4618]
Dong, J.-T., Lamb, P. W., Rinker-Schaeffer, C. W., Vukanovic, J., Ichikawa, T., Isaacs, J. T., Barrett, J. C. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 268: 884-886, 1995. [PubMed: 7754374] [Full Text: https://doi.org/10.1126/science.7754374]
Guo, X.-Z., Friess, H., Di Mola, F. F., Heinicke, J.-M., Abou-Shady, M., Graber, H. U., Baer, H. U., Zimmermann, A., Korc, M., Buchler, M. W. KAI1, a new metastasis suppressor gene, is reduced in metastatic hepatocellular carcinoma. Hepatology 28: 1481-1488, 1998. [PubMed: 9828210] [Full Text: https://doi.org/10.1002/hep.510280606]
Ichikawa, T., Ichikawa, Y., Dong, J., Hawkins, A. L., Griffin, C. A., Isaacs, W. B., Oshimura, M., Barrett, J. C., Isaacs, J. T. Localization of metastasis suppressor gene(s) for prostatic cancer to the short arm of human chromosome 11. Cancer Res. 52: 3486-3490, 1992. [PubMed: 1596907]
Ichikawa, T., Ichikawa, Y., Isaacs, J. T. Genetic factors and suppression of metastatic ability of prostatic cancer. Cancer Res. 51: 3788-3792, 1991. [PubMed: 2065333]
Jee, B. K., Park, K. M., Surendran, S., Lee, W. K., Han, C. W., Kim, Y. S., Lim, Y. KAI1/CD82 suppresses tumor invasion by MMP9 inactivation via TIMP1 up-regulation in the H1299 human lung carcinoma cell line. Biochem. Biophys. Res. Commun. 342: 655-661, 2006. [PubMed: 16488391] [Full Text: https://doi.org/10.1016/j.bbrc.2006.01.153]
Kim, J. H., Kim, B., Cai, L., Choi, H. J., Ohgi, K. A., Tran, C., Chen, C., Chung, C. H., Huber, O., Rose, D. W., Sawyers, C. L., Rosenfeld, M. G., Baek, S. H. Transcriptional regulation of a metastasis suppressor gene by Tip60 and beta-catenin complexes. Nature 434: 921-926, 2005. Note: Erratum: Nature 607: E11, 2022. [PubMed: 15829968] [Full Text: https://doi.org/10.1038/nature03452]
Mashimo, T., Watabe, M., Hirota, S., Hosobe, S., Miura, K., Tegtmeyer, P. J., Rinker-Shaeffer, C. W., Watabe, K. The expression of the KAI1 gene, a tumor metastasis suppressor, is directly activated by p53. Proc. Nat. Acad. Sci. 95: 11307-11311, 1998. [PubMed: 9736732] [Full Text: https://doi.org/10.1073/pnas.95.19.11307]
Miyazaki, T., Kato, H., Shitara, Y., Yoshikawa, M., Tajima, K., Masuda, N., Shouji, H., Tsukada, K., Nakajima, T., Kuwano, H. Mutation and expression of the metastasis suppressor gene KAI1 in esophageal squamous cell carcinoma. Cancer 89: 955-962, 2000. [PubMed: 10964324] [Full Text: https://doi.org/10.1002/1097-0142(20000901)89:5<955::aid-cncr3>3.0.co;2-z]
Tsai, Y. C., Mendoza, A., Mariano, J. M., Zhou, M., Kostova, Z., Chen, B., Veenstra, T., Hewitt, S. M., Helman, L. J., Khanna, C., Weissman, A. M. The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nature Med. 13: 1504-1509, 2007. [PubMed: 18037895] [Full Text: https://doi.org/10.1038/nm1686]
Virtaneva, K. I., Angelisova, P., Baumruker, T., Horejsi, V., Nevanlinna, H., Schroder, J. The genes for CD37, CD53, and R2, all members of a novel gene family, are located on different chromosomes. Immunogenetics 37: 461-465, 1993. [PubMed: 8436422] [Full Text: https://doi.org/10.1007/BF00222471]