Article

Dissecting the diverse functions of the metastasis suppressor CD82/KAI1

Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States.
FEBS letters (Impact Factor: 3.34). 08/2011; 585(20):3166-73. DOI: 10.1016/j.febslet.2011.08.031
Source: PubMed

ABSTRACT The recent identification of metastasis suppressor genes, the products of which inhibit metastasis but not primary tumor growth, distinguishes oncogenic transformation and tumor suppression from a hallmark of malignancy, the ability of cancer cells to invade sites distant from the primary tumor. The metastasis suppressor CD82/KAI1 is a member of the tetraspanin superfamily of glycoproteins. CD82 suppresses metastasis by multiple mechanisms including inhibition of cell motility and invasion, promotion of cell polarity as well as induction of senescence and apoptosis in response to extracellular stimuli. A common feature of these diverse effects is CD82 regulation of membrane organization as well as protein trafficking and interactions, which affects cellular signaling and intercellular communication.

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    • "Among them, the tumor suppressor CD82 was up-regulated by WT EGFR but down-regulated by mutant EGFRs, which is intriguing. CD82, a member of the teraspanin family, is a cancer metastasis suppressor and is often down-regulated in cancers [15] [16] [17] [18]. Moreover, CD82 expression is correlated with a good prognosis in non-small cell lung cancer (NSCLC) patients [19]. "
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    ABSTRACT: Epidermal growth factor receptor (EGFR) gene mutations are strongly associated with lung adenocarcinoma and favorable response to EGFR tyrosine kinase inhibitor. The mutated EGFR proteins (EGFRs) are hyper-phosphorylated and refractory to receptor down-regulation. To address the discrepancy between hyper-phosphorylation and lack of down-regulation of mutant EGFRs, we have examined the expression of EGFR negative regulators in non-small cell lung cancer (NSCLC) cell lines. We found that NSCLC cell lines expressing mutant EGFRs often had low expression of various negative regulators for EGFR. Among them, tumor suppressor CD82 was up-regulated by wild type (WT) EGFR but down-regulated by mutant EGFRs. Reconstitution of CD82 exerted stronger suppressive effects on mutant EGFRs than on WT EGFR. Active exportation of CD82 through exosome was one of the mechanisms involved in achieving the overall CD82 down-regulation in mutant EGFR-expressing lung cancer cell lines. Over-expression of mutant EGFR protein frequently occurred in the lung cancer tissues of mutant EGFR-transgenic mice and also associated with CD82 down-regulation. Immunoblot analyses on the tumor tissues from 23 lung adenocarcinoma patients (12 with WT EGFR, and 11 with mutant EGFRs) also identified significantly stronger down regulation of CD82 in tumors with mutant EGFRs than WT. Our data indicate that CD82 down-regulation could be a critical step involved in the EGFR over-expression and the stronger tumorigenic activity triggered by EGFR mutations. Up-regulation of the CD82 level may become a promising new treatment strategy for lung adenocarcinoma.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 04/2015; 7(7). DOI:10.1016/j.bbadis.2015.04.020 · 5.09 Impact Factor
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    • "Expression of MSGs is frequently reduced in highly metastatic tumor cells [6]. The MSG KAI1 has previously been shown to interfere with multiple steps of the metastatic cascade, including proliferation, invasion, and migration, making it an attractive marker to evaluate in UM and other cancers [7] [8]. Multiple studies have demonstrated that the expression of KAI1 in some primary tumor types is inversely correlated with formation of metastasis [9]. "
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    ABSTRACT: Introduction. Uveal melanoma (UM) is an intraocular tumor that leads to metastatic disease in approximately 50% of afflicted patients. There is no efficacious treatment for metastatic disease in this cancer. Identification of markers that can offer prognostic and therapeutic value is a major focus in this field at present. KAI1 is a metastasis suppressor gene that has been reported to play a role in various human malignancies, although it has not previously been evaluated in UM. Purpose. To investigate the expression of KAI1 in UM and its potential value as a prognostic marker. Materials and Methods. 18 cases of human primary UM were collected and immunostained for KAI1 expression. A pathologist evaluated staining intensity and distribution semiquantitatively. Each case was categorized as group 1 (low staining) or group 2 (high staining). Results. In group 2, two of the 12 cases presented with metastasis. Conversely, in group 1, five out of 6 cases had metastasis. The mean follow-up of patients who did not develop metastasis was 81.81 months (median: 75 months) versus 42.14 months (median: 44 months) for patients with metastasis. Conclusions. KAI1 is a promising candidate marker that may offer prognostic value in UM; it may also represent a therapeutic target in metastatic disease.
    Journal of Ophthalmology 08/2013; 2013:683963. DOI:10.1155/2013/683963 · 1.94 Impact Factor
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    • "Knopeke et al. [3] highlight the biological mechanism of action of MAP kinase kinase 4 (MKK4), specifically its valuable use in disrupting tumor cell-microenvironment interactions to elucidate the requirements for metastatic colonization and developing models to allow the study on early steps of dormancy. Tsai and Weissman [4] are dealing with the multiple mechanisms implicated in metastasis suppression by CD82/KAI1, a member of the tetraspanin superfamily of glycoproteins affecting membrane organization, protein interactions and hence cell signaling and intercellular communication. The Nm23 family of metastasis-associated genes particularly the Nm23-H1 anti-metastatic factor is in focus of Saha and Roberts' contribution [5]. "
    FEBS letters 09/2011; 585(20):3147. DOI:10.1016/j.febslet.2011.09.022 · 3.34 Impact Factor
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