Coexpression of Integrin αvβ3 and Matrix Metalloproteinase-2 (MMP-2) Coincides with MMP-2 Activation: Correlation with Melanoma Progression

Hofmann, U.; Westphal, Johan R.; Waas, Erwin T.; Becker, Jürgen C.; Ruiter, Dirk J.; Muijen, G.N.P. van

doi:10.1046/j.1523-1747.2000.00114.x

Cited by 93 publications

(75 citation statements)

References 42 publications

(49 reference statements)

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“…To analyze whether phosphorylation of L-plastin might be important to promote tumor progression, we used the L-plastin negative human melanoma cell line MV3 8,[29][30][31][32][33][34][35][36][37] to generate stable L-plastin expressing cell populations. MV3 cells were either transfected with a cDNA encoding EGFP alone (control), or the entire L-plastin sequence fused to EGFP (wt-LPL-EGFP), or a mutated version of L-plastin where Ser5 and Ser7, the only known phosphorylation sites of L-plastin [20][21][22] were changed to Ala (5A7A-LPL-EGFP) to prevent phosphorylation (Fig.…”

Section: Generation Of Melanoma Cell Populations Stably Expressing Eimentioning

confidence: 99%

“…4,5,7 In human melanoma, especially b1-and b3-subunit containing integrins play important roles in metastasis, through an enhancement of adhesion, migration and invasion. 8,9 Moreover, the cell surface expression levels of many integrins can be directly correlated with the metastatic potential of melanoma cells. [10][11][12] Modulation of the actin cytoskeleton is critical for integrin function and tumor cell migration and invasion.…”

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confidence: 99%

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Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

Klemke

Rafael

Wabnitz

et al. 2007

Intl Journal of Cancer

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The leukocyte specific actin-binding protein L-plastin is aberrantly expressed in several nonhematopoetic malignant tumors. However, little is known about the functional consequences of Lplastin expression. Here, we investigated the function of L-plastin in human malignant melanoma cells. Knock-down of endogenous L-plastin by siRNA treatment reduced migration of the melanoma cell line IF6. However, in melanoma patients, no correlation existed between L-plastin expression and tumor stages. This implied that additional factors such as phosphorylation of L-plastin may influence its function in tumor cells. To investigate this further, EGFP-tagged wild-type L-plastin (wt-LPL-EGFP) and a mutated, nonphosphorylatable L-plastin protein (5A7A-LPL-EGFP), were expressed in the L-plastin negative melanoma cell line MV3. Biochemical analysis revealed that wt-LPL-EGFP is phosphorylated in MV3 cells while 5A7A-LPL-EGFP is not. Although both wt-LPL-EGFP and 5A7A-LPL-EGFP were targeted to, and promote the formation of, vinculin-containing adhesion sites, static adhesion to either Matrigel or isolated extracellular matrix molecules was neither influenced by expression of wt-LPL-EGFP nor by expression of 5A7A-LPL-EGFP when compared with EGFP expressing control cells. In contrast, haptotactic, but not chemotactic, migration of melanoma cells towards either Matrigel or isolated extracellular matrix molecules was similarly enhanced, if either 5A7A-LPL-EGFP or wt-LPL-EGFP were expressed in MV3 cells. Interestingly, only cells expressing the phosphorylatable wt-LPL-EGFP protein showed enhanced invasion into Matrigel. In line with these findings the in vivo metastatic capacity of mouse B16 melanoma cells correlates with expression and phosphorylation of L-plastin. These data show that an increase in melanoma cell invasiveness requires not only expression but also phosphorylation of L-plastin. ' 2007 Wiley-Liss, Inc.Key words: migration; invasion; adhesion; L-plastin; melanoma Malignant melanoma is a very aggressive type of cancer that frequently metastasizes to distant organs. The capacity of tumor cells to form metastatic foci correlates with the ability to proteolytically degrade basement membrane barriers and to adhere to and migrate through extracellular matrix layers. 1,2 Two classes of molecules are mainly involved in these processes: the matrix metalloproteinases (MMPs) 3 and integrins. 4,5 Integrins are a large family of adhesion receptors involved in cell-cell and cellextracellular matrix interactions. They consist of heterodimers of 2 noncovalently associated a-and b-subunits. 6 The role of integrins in tumor cell metastasis has been intensively studied. 4,5,7 In human melanoma, especially b1-and b3-subunit containing integrins play important roles in metastasis, through an enhancement of adhesion, migration and invasion. 8,9 Moreover, the cell surface expression levels of many integrins can be directly correlated with the metastatic potential of melanoma cells. [10][11][12] Modulation of the actin cytoskeleton is critical f...

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Section: Generation Of Melanoma Cell Populations Stably Expressing Eimentioning

confidence: 99%

mentioning

confidence: 99%

Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

Klemke

Rafael

Wabnitz

et al. 2007

Intl Journal of Cancer

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“…As repeatedly described, the increased coexpression of a subset of matrix metalloproteinases (MMP-2, MT1-MMP) and integrin b3 is correlated with early melanoma invasion. [15][16][17][18] The inductio n of MMP-1 is reported to be a late event marker during cell invasion of advanced melanomas. 19 The signal distribution of MMP-1, MMP-2, MT1-MMP and integrin b3 revealed a complex expression pattern, notably in both analyzed entities.…”

Section: Immunohistochemical Staining Of Markers Representing Invasivmentioning

confidence: 99%

Loss of dipeptidyl peptidase IV immunostaining discriminates malignant melanomas from deep penetrating nevi

Roesch¹,

Wittschier²,

Becker³

et al. 2006

Modern Pathology

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The deep penetrating nevus is a rare variant of benign melanocytic nevus with histologic features mimicking vertical growth phase, nodular malignant melanoma. In this study, we expand on the search for new complementary discriminating markers by analyzing a selection of both cell cycle-related factors, such as retinoblastoma protein and phospho-retinoblastoma protein Ser795 as indicators for retinoblastoma protein activation/inactivation status, and invasion-related factors, such as matrix metalloproteinase-1, matrix metalloproteinase-2, membrane-type matrix metalloproteinase-1 and integrin b3. MIB-1/Ki-67 was analyzed as an example for a common proliferation marker. Dipeptidyl peptidase IV/CD26 was analyzed as a marker affecting both proliferation and invasion of malignant melanocytic tumors. Semiquantitative assessment of both immunolocalization and immunoreactivity of retinoblastoma protein and phospho-retinoblastoma protein Ser795, MIB-1/Ki-67, matrix metalloproteinase-1, matrix metalloproteinase-2, membrane-type matrix metalloproteinase-1 and integrin b3 revealed no consistent differences between deep penetrating nevi (n ¼ 14) and matched cases of nodular malignant melanomas (n ¼ 10). Matrix metalloproteinase-1 and matrix metalloproteinase-2 immunostaining of some deep penetrating nevi even exceeded that of nodular malignant melanomas. Membrane-type matrix metalloproteinase-1 expression scores of nodular malignant melanomas were higher than those of deep penetrating nevi, which was, however, not significantly discriminative. In contrast, immunostaining of dipeptidyl peptidase IV was significantly discriminative due to a consistent lack of dipeptidyl peptidase IV-expression in nodular malignant melanomas. These results add evidence that among the selected markers supposed to be relevant for melanoma progression the presence of dipeptidyl peptidase IV can be used to support diagnosis of deep penetrating nevi in doubtful cases. As loss of dipeptidyl peptidase IV may also be causally linked to the transition of invasive to metastatic phenotypes, the molecular mechanisms downstream of dipeptidyl peptidase IV deserve to be studied in more detail in future investigations.

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“…Since a coordinated interplay between adhesion molecules and metalloproteases has been reported in both vascular remodelling and tumor invasion (Hofmann et al, 2000), matrix metalloprotease (MMP)-2 and MMP-9 expression was analysed in the transduced vs control cell lines. Interestingly, MMP-9 was downregulated in all PLZFexpressing melanomas as compared with the empty (Figure 7 and not shown).…”

Section: Expression Of Plzf-regulated Genesmentioning

confidence: 99%

Role of PLZF in melanoma progression

et al. 2004

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The promyelocytic leukemia zinc finger (PLZF) protein has been described as a transcriptional repressor of homeobox (HOX)-containing genes during embryogenesis. As we previously demonstrated a functional link between overexpression of HOXB7 and melanoma progression, we investigated the lack of PLZF as the possible cause of HOXB7 constitutive activation in these neoplastic cells. Accordingly, we found PLZF expression in melanocytes, but not in melanoma cells, a pattern inversely related to that of HOXB7. PLZF retroviral gene transduction was then performed in a panel of melanoma cell lines, and tumorigenicity was compared with that of empty vector-transduced control cell lines. Evaluation of in vitro migration, invasion and adhesion indicated that PLZF gene transduction induced a less malignant phenotype, as confirmed through in vivo studies performed in athymic nude mice. This reduced tumorigenicity was not coupled with HOXB7 repression. In order to find more about the molecular targets of PLZF, the gene expression profiles of PLZF-and empty vector-transduced A375 melanoma cells were analysed by Atlas Cancer macroarray. Among several genes modulated by PLZF enforced expression, of particular interest were integrin avb3, osteonectin/SPARC and matrix metalloprotease-9 that were downmodulated, and the tyrosinase-related protein-1 that was upregulated in all the analysed samples. This profile confirms the reduced tumorigenic phenotype with reversion to a more differentiated, melanocyte like, pattern, thus suggesting a suppressor role for PLZF in solid tumors. Moreover, these results indicate that PLZF and HOXB7 are functionally independent and that their coupled deregulation may account for most of the alterations described in melanomas.

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Coexpression of Integrin αvβ3 and Matrix Metalloproteinase-2 (MMP-2) Coincides with MMP-2 Activation: Correlation with Melanoma Progression

Cited by 93 publications

References 42 publications

Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

Loss of dipeptidyl peptidase IV immunostaining discriminates malignant melanomas from deep penetrating nevi

Role of PLZF in melanoma progression

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