Motility‐related protein 1 (MRP‐1/CD9) expression in urothelial bladder carcinoma and its relation to tumor recurrence and progression

Mhawech, Paulette; Herrmann, Françoís; Coassin, Marco; Guillou, Louis; Iselin, Christophe

doi:10.1002/cncr.11698

Cited by 34 publications

(24 citation statements)

References 64 publications

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“…MRP-1 is known as a membrane glycoprotein identical to the CD9 antigen (24 kD) and it belongs to a structurally distinct family of cell membrane glycoproteins. As for relationship of MRP-1 with malignancies, the reduced MRP-1 expression was significantly associated with high grade and lower diseasefree survival in 153 cases of head and neck cancer and 111 cases of urothelial bladder carcinoma [17,18]. In addition, Hashida et al described that the overall survival rate of patients with MRP-1-positive tumors was much higher than that of patients with MRP-1-negative tumors in 146 cases of colorectal cancer.…”

Section: Discussionmentioning

confidence: 95%

Identification of molecular markers for metastasis-related genes in primary breast cancer cells

Mimori

Kataoka

Yoshinaga

et al. 2005

Clin Exp Metastasis

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Comparing differential gene expression profiles established by cDNA microarray between normal cells (N), primary carcinoma cells (T), and metastatic carcinoma cells (M) may determine those critical genes directly associated with progression and metastasis of breast cancer. Total RNA was extracted by laser microdissection (LMD) from 20 slices of T, N and M from 6 cases. After amplification by a T7-based system, differentially expressed genes between T, N and M were identified by cDNA microarray. In addition, to clarify the mechanism for altered gene expression, we determined the methylation status by sequencing after bisulfite treatment for intriguing genes. As a result, the expression of motility related protein-1 (MRP-1/CD9), peripheral myelin protein-22 (PMP-22), and caspase 3 (CASP-3) were down-regulated in M compared to T. We focused especially on MRP-1 and found that the expression status of MRP-1 was significantly inversely associated with stage of disease in 56 cases of breast cancer (P<0.05), and the relapse free survival in 5 years was significantly higher in MRP-1 positive cases than those negative cases (P<0.05). Conversely, overexpression, by 11-fold, of signal transduction and translation factors were observed in T compared to N. The cancer specific methylation was observed only in CASP-3 in a case. In conclusion, the establishment of the present assay allows us to detect genes directly associated with each cell population within tumor tissue and gives us clues to identify metastasis-related genes comprehensively in clinical breast cancer cases.

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Section: Discussionmentioning

confidence: 95%

Identification of molecular markers for metastasis-related genes in primary breast cancer cells

Mimori

Kataoka

Yoshinaga

et al. 2005

Clin Exp Metastasis

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“…Decreased expression of CD9 (46) and CD82 (47) in urothelial cancer was recently reported to be associated with recurrence and increased metastasis. However, detailed study on CD9 indicates that CD9 alone does not inhibit tumor cell motility or invasiveness; rather, such inhibition requires GM3 and complete N-glycosylation, including that of integrin.…”

Section: Discussionmentioning

confidence: 98%

A Specific Microdomain (“Glycosynapse 3”) Controls Phenotypic Conversion and Reversion of Bladder Cancer Cells through GM3-mediated Interaction of α3β1 Integrin with CD9

Mitsuzuka

Handa

Satoh

et al. 2005

Journal of Biological Chemistry

110

104

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Human bladder cancer cell lines KK47 (noninvasive and nonmetastatic) and YTS1 (highly invasive and metastatic), both derived from transitional bladder epithelia, are very similar in terms of integrin composition and levels of tetraspanin CD9. Tetraspanin CD82 is absent in both. The major difference is in the level of ganglioside GM3, which is several times higher in KK47 than in YTS1. We now report that the GM3 level reflects glycosynapse function as follows: (i) a stronger interaction of integrin ␣3 with CD9 in KK47 than in YTS1; (ii) conversion of benign, low motility KK47 to invasive, high motility cells by depletion of GM3 by P4 (D-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol) treatment or by knockdown of CD9 by the RNA interference method; (iii) reversion of high motility YTS1 to low motility phenotype like that of KK47 by exogenous GM3 addition, whereby the ␣3-to-CD9 interaction was enhanced; (iv) low GM3 level activated c-Src in YTS1 or in P4-treated KK47, and high GM3 level by exogenous addition caused Csk translocation into glycosynapse, with subsequent inhibition of c-Src activation; (v) inhibition of c-Src by "PP2" in YTS1 greatly reduced cell motility. Thus, GM3 in glycosynapse 3 plays a dual role in defining glycosynapse 3 function. One is by modulating the interaction of ␣3 with CD9; the other is by activating or inhibiting the c-Src activity, possibly through Csk translocation. High GM3 level decreases tumor cell motility/invasiveness, whereas low GM3 level enhances tumor cell motility/invasiveness. Oncogenic transformation and its reversion can be explained through the difference in glycosynapse organization.

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“…The latter result could help to explain CD9 tumor suppressor properties. Indeed, CD9 expression is often markedly reduced in malignant melanoma (13), colon (14), bladder (15), lung (16), pancreatic (17), squamous cell (18,19), and breast cancers (20,21). Furthermore, CD9 signaling can decrease cell proliferation while promoting apoptosis (22), and ectopic CD9 can suppress tumor cell motility and metastasis (23,24), and down-regulate Wnt signaling pathways (25).…”

mentioning

confidence: 99%

Contrasting Effects of EWI Proteins, Integrins, and Protein Palmitoylation on Cell Surface CD9 Organization

Yang

Коваленко

Kolesnikova

et al. 2006

Journal of Biological Chemistry

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CD9, a tetraspanin protein, makes crucial contributions to sperm egg fusion, other cellular fusions, epidermal growth factor receptor signaling, cell motility, and tumor suppression. Here we characterize a low affinity anti-CD9 antibody, C9BB, which binds preferentially to homoclustered CD9. Using mAb C9BB as a tool, we show that cell surface CD9 homoclustering is promoted by expression of ␣3␤1 and ␣6␤4 integrins and by palmitoylation of the CD9 and ␤4 proteins. Conversely, CD9 is shifted toward heteroclusters upon expression of CD9 partner proteins (EWI-2 and EWI-F) or other tetraspanins, or upon ablation of CD9 palmitoylation. Furthermore, unpalmitoylated CD9 showed enhanced EWI-2 association, thereby demonstrating a previously unappreciated role for tetraspanin palmitoylation, and underscoring how depalmitoylation and EWI-2 association may collaborate to shift CD9 from homo-to heteroclusters. In conclusion, we have used a novel molecular probe (mAb C9BB) to demonstrate the existence of multiple types of CD9 complex on the cell surface. A shift from homo-to heteroclustered CD9 may be functionally significant because the latter was especially obvious on malignant epithelial tumor cells. Hence, because of its specialized properties, C9BB may be more useful than other anti-CD9 antibodies for monitoring CD9 during tumor progression.Tetraspanin protein CD9 has attracted considerable attention for its crucial role on oocytes during sperm egg fusion (1-3). CD9 also contributes to myoblast fusion (4) mononuclear phagocyte fusion (5), virus-induced syncytia formation (6, 7), osteoclastogenesis (5), and paranodal junction formation in the peripheral nervous system (8). CD9 also promotes juxtacrine signaling by associating with epidermal growth factor (EGF) receptor membrane-bound agonists, pro-TGF␣, pro-HB-EGF, and pro-amphiregulin (9 -11). CD9 may affect paracrine signaling by either promoting (12) or inhibiting (9) proteolytic production of soluble EGF receptor agonist. The latter result could help to explain CD9 tumor suppressor properties. Indeed, CD9 expression is often markedly reduced in malignant melanoma (13), colon (14), bladder (15), lung (16), pancreatic (17), squamous cell (18,19), and breast cancers (20,21). Furthermore, CD9 signaling can decrease cell proliferation while promoting apoptosis (22), and ectopic CD9 can suppress tumor cell motility and metastasis (23, 24), and down-regulate Wnt signaling pathways (25).Tetraspanins typically assemble into multimolecular membrane complexes. In this regard, CD9 can directly associate with transmembrane Ig superfamily proteins EWI 2 -F (CD9P-1, FPRP) and EWI-2 (26 -29), which can drive CD9 into filopodia (32). CD9 also directly associates with itself, suggesting that CD9-CD9 homodimers are building blocks for larger tetraspanin complexes (30). Additional partners for CD9 include the laminin-binding integrins ␣3␤1, ␣6␤1, and ␣6␤4 (31). One consequence of integrin-CD9 association is the recruitment of EWI-2, via CD9, into a functionally important EWI2-CD9-integrin ...

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Motility‐related protein 1 (MRP‐1/CD9) expression in urothelial bladder carcinoma and its relation to tumor recurrence and progression

Cited by 34 publications

References 64 publications

Identification of molecular markers for metastasis-related genes in primary breast cancer cells

Identification of molecular markers for metastasis-related genes in primary breast cancer cells

A Specific Microdomain (“Glycosynapse 3”) Controls Phenotypic Conversion and Reversion of Bladder Cancer Cells through GM3-mediated Interaction of α3β1 Integrin with CD9

Contrasting Effects of EWI Proteins, Integrins, and Protein Palmitoylation on Cell Surface CD9 Organization

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