Frequent downregulation of the KAI1(CD82) metastasis suppressor protein in human cancer cell lines

White, Ayla O.; Lamb, Patricia W.; Barrett, J. Carl

doi:10.1038/sj.onc.1201852

Cited by 67 publications

(48 citation statements)

References 12 publications

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“…Almost all NSCLC cell lines are CD9-positive although the mean fluorescence intensity was variable (Table 1 and data not shown). This observation is consistent with a previous report that examined CD9, CD81, and CD82 expressions in various cancer cell lines, and showed that most NSCLC Tetraspanins in human lung cancer cells T Funakoshi et al lines (10 of 11) expressed CD9 (White et al, 1998). Among the NSCLC lines tested in the present study, only VMRC-LCD lacked CD9.…”

Section: Discussionsupporting

confidence: 82%

“…The cells were then incubated at 371C, 10% CO 2 , and monitored using an inverted fluorescence microscope, Diaphoto (Nikon, Tokyo, Japan) equipped with an SVHS video recorder (Sony, Tokyo, Japan) for 2 h (Kashii et al, 1992;White et al, 1998). The tracks and distances of random motility of at least 30 cells were obtained by the microcomputer imaging device (MCID) (Imaging Research, Ontario, Canada) using the program, Image Analyzer (Ver.…”

Section: Boyden Chamber Cell Motility Assaymentioning

confidence: 99%

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Expression of tetraspanins in human lung cancer cells: frequent downregulation of CD9 and its contribution to cell motility in small cell lung cancer

et al. 2003

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Small cell lung cancer (SCLC) invades locally and metastasizes distantly extremely early when compared with nonsmall cell lung cancer (NSCLC). The underlying molecular mechanisms, however, have not been elucidated. Accumulating evidence suggests that downregulation of several members of tetraspanins is associated with progression of solid tumors, thus indicating poor prognosis. Here we screened 30 lung cancer cell lines for expression of tetraspanins, CD9, CD63, CD81, CD82, CD151, and NAG-2. Flow cytometry revealed that, among these proteins, CD9 is broadly expressed in NSCLC lines, but is absent or highly reduced in most SCLC lines (Po0.0001). Using the Boyden chamber and videomicroscopic cell motility assays, we showed that stable transfection of CD9 into an SCLC line, OS3-R5, reduced cell motility on fibronectin. Furthermore, by transient transfection of green fluorescent protein (GFP)-tagged CD9 into three other SCLC lines, we observed that SCLC cells expressing GFP-CD9 were uniformly less motile than untransfected cells. CD9 or GFP-CD9 was associated with b1 integrins and distributed at the tumor cell periphery and cell-cell contacts, suggesting that CD9 modifies b1 integrin function to reduce motility. These findings suggest that low expression of CD9 may contribute to the highly invasive and metastatic phenotype of SCLC.

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Section: Discussionsupporting

confidence: 82%

Section: Boyden Chamber Cell Motility Assaymentioning

confidence: 99%

Expression of tetraspanins in human lung cancer cells: frequent downregulation of CD9 and its contribution to cell motility in small cell lung cancer

et al. 2003

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“…Loss or low expression has been shown to correlate with poor prognosis in lung (Adachi et al, 1996), pancreatic (Guo et al, 1996), breast (Huang et al, 1998), bladder (Yu et al, 1997), colon (Lombardi et al, 1999), esophageal (Uchida et al, 1999;Miyazaki et al, 2000), cervical (Liu et al, 2001), ovarian , and endometrial cancers. Downregulation of CD82 expression has also been observed in many metastatic tumor cell lines (White et al, 1998).…”

Section: Introductionmentioning

confidence: 94%

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

2005

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KAI1/CD82, a tetraspanin protein, was first identified as a metastasis suppressor in prostate cancer. How loss of CD82 expression promotes cancer metastasis is unknown. Restoration of CD82 expression to physiological levels in the metastatic prostate cell line PC3 inhibits integrinmediated cell migration and invasion, but does not affect integrin expression. Integrin-dependent activation of the receptor kinase c-Met is dramatically reduced in CD82-expressing cells, as is c-Met activation by its ligand HGF/ SF. CD82 expression also reduced integrin-induced activation and phosphorylation of the cytoplasmic tyrosine kinase Src, and its downstream substrates p130Cas and FAK Y861. Inhibition of c-Met expression or Src kinase function reduced matrigel invasion of PC3 cells to the same extent as CD82 expression. These data indicate that CD82 functions to suppress integrin-induced invasion by regulating signaling to c-Met and Src kinases, and suggests that CD82 loss may promote metastasis by removing a negative regulator of c-Met and Src signaling.

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“…In UACC-893, G2 detected KAI1 as a typical band smear, which is due to variable N-linked glycosylation of KAI1. 8,14 Using formalin-fixed paraffin-embedded UACC-893 and MCF-7 cells, immunohistochemical staining of KAI1 was optimized (Fig. 1c).…”

Section: Establishment Of An Optimized Immunohistochemical Staining Omentioning

confidence: 99%

“…[5][6][7] In line with this, human prostate cancer and melanoma cell lines of metastatic origin lack expression of KAI1. 8 Therefore, KAI1 is widely perceived as a metastasis suppressor and has been suggested to represent a promising biomarker for the metastatic potential in human malignancies. 9,10 Yet, several lines of evidence indicate that KAI1 also functions as a suppressor of primary tumor growth.…”

mentioning

confidence: 99%

KAI1/CD82 is a novel target of estrogen receptor‐mediated gene repression and downregulated in primary human breast cancer

Christgen¹,

Bruchhardt²,

Ballmaier³

et al. 2008

Intl Journal of Cancer

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The cell-surface glycoprotein KAI1 suppresses tumor growth and metastasis in various animal models. Downregulation of KAI1 has been implicated in the progression of cancer. However, the mechanisms of KAI1 inactivation are poorly understood. This is the first study that investigates expression and regulation of KAI1 in human breast cancer. KAI1 expression was analyzed on custommade tissue microarrays comprising 209 well-characterized breast cancers and normal mammary gland tissue. Strong KAI1 immunoreactivity was observed throughout the normal mammary gland epithelium. In breast cancer tissue, KAI1 immunoreactivity was lost in 161/209 (77%) cases. Strikingly, KAI1 was preferentially lost in estrogen receptor (ER)-positive breast cancers (p < 0.001). This was validated by real-time RT-PCR analyses showing a 7.5-fold downregulation of KAI1 mRNA in ER-positive relative to ERnegative tumors (p 5 0.028). Notably, this was also corroborated by Affymetrix microarray expression data of an independent cohort of 49 breast cancers. Class comparison analysis identified KAI1 as downregulated in ER-positive tumors. Subsequently, human breast cancer cell lines were employed to test a potential role of ER-activity in the downregulation of KAI1, as suggested by our expression analyses. Exposure of ER-positive breast cancer cells to fulvestrant, a clinically approved ER-antagonist that reverses ER-mediated gene repression, induced a significant upregulation of KAI1 and inhibited cell proliferation as well as migration. In summary, we demonstrate for the first time that KAI1 is a target of ER-mediated gene-repression, and thus, it is downregulated in ER-positive breast cancer. Importantly, KAI1 might be reinducible by endocrine therapy with ER-antagonists in patients suffering from ER-positive breast cancer. ' 2008 Wiley-Liss, Inc.Key words: KAI1; breast cancer; fulvestrant; faslodex; microarray KAI1, also known as CD82, is a member of the tetraspanin or transmembrane 4 superfamily (TM4SF) of cell-surface glycoproteins. TM4SF proteins are involved in fundamental cellular processes, such as cell-cell interaction, cell motility and proliferation. 1 KAI1 is expressed by epithelial cells and is gradually downregulated or lost in prostate cancer. [2][3][4] Ectopic expression of KAI1 suppresses the metastatic phenotype of AT6.1 and LNCaP prostate cancer cells and of B16BL6 melanoma cells in experimental animal models. [5][6][7] In line with this, human prostate cancer and melanoma cell lines of metastatic origin lack expression of KAI1. 8 Therefore, KAI1 is widely perceived as a metastasis suppressor and has been suggested to represent a promising biomarker for the metastatic potential in human malignancies. 9,10 Yet, several lines of evidence indicate that KAI1 also functions as a suppressor of primary tumor growth. 11 Reestablishment of KAI1 expression in KAI1-negative cancer cells tremendously impairs tumor formation at the injection site in nude mice. 11 In addition, downregulation of KAI1 in prostate cancer is already evident in pr...

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Frequent downregulation of the KAI1(CD82) metastasis suppressor protein in human cancer cell lines

Cited by 67 publications

References 12 publications

Expression of tetraspanins in human lung cancer cells: frequent downregulation of CD9 and its contribution to cell motility in small cell lung cancer

Expression of tetraspanins in human lung cancer cells: frequent downregulation of CD9 and its contribution to cell motility in small cell lung cancer

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

KAI1/CD82 is a novel target of estrogen receptor‐mediated gene repression and downregulated in primary human breast cancer

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