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Tumor-derived microvesicles mediate human breast cancer invasion through differentially glycosylated EMMPRIN.

Menck K, Scharf C, Bleckmann A, Dyck L, Rost U, Wenzel D, Dhople VM, Siam L, Pukrop T, Binder C, Klemm F - J Mol Cell Biol (2014)

Bottom Line: Uptake of T-MV is essential for the proinvasive effect.Interestingly, the effect of EMMPRIN-bearing MV is not mediated by matrix metalloproteinases but by activation of the p38/MAPK signaling pathway in the tumor cells.In conclusion, T-MV stimulate cancer cell invasion via a direct feedback mechanism dependent on highly glycosylated EMMPRIN.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany.

No MeSH data available.


Related in: MedlinePlus

p38 signal transduction partially mediates MV-induced cancer cell invasion. (A) MMP mRNA expression in MCF-7 cells stimulated for 24 h with MV (25 µg/ml) (qRT–PCR, mean ± SD, n = 3). (B) Zymography for MMP-9 in tumor and benign cells (C), as well as their respective MV (SK, SK-BR-3; MΦ, human macrophages; P, platelets). (C) Western blots showing the phosphorylation of p38 and c-jun in MCF-7 cells stimulated with T-MV for the indicated time periods. (D) Analysis of p38 phosphorylation in MCF-7 cells incubated for 1 h with T-MV from EMMPRIN knockdown (shEMP) or non-sense control (ns) cells. (E) Microinvasion assay of MCF-7 cells pretreated with the p38 inhibitor SB-203580 (SB) for 2 h followed by stimulation with T-MV (1 µg/ml) (mean ± SD, n = 3, *P < 0.001). (F) Western blots showing p38 phosphorylation in MCF-7 cells pretreated with two EMMPRIN blocking peptides P-N160 and P-N268, respectively, for 2 h prior to stimulation with T-MV.
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MJU047F6: p38 signal transduction partially mediates MV-induced cancer cell invasion. (A) MMP mRNA expression in MCF-7 cells stimulated for 24 h with MV (25 µg/ml) (qRT–PCR, mean ± SD, n = 3). (B) Zymography for MMP-9 in tumor and benign cells (C), as well as their respective MV (SK, SK-BR-3; MΦ, human macrophages; P, platelets). (C) Western blots showing the phosphorylation of p38 and c-jun in MCF-7 cells stimulated with T-MV for the indicated time periods. (D) Analysis of p38 phosphorylation in MCF-7 cells incubated for 1 h with T-MV from EMMPRIN knockdown (shEMP) or non-sense control (ns) cells. (E) Microinvasion assay of MCF-7 cells pretreated with the p38 inhibitor SB-203580 (SB) for 2 h followed by stimulation with T-MV (1 µg/ml) (mean ± SD, n = 3, *P < 0.001). (F) Western blots showing p38 phosphorylation in MCF-7 cells pretreated with two EMMPRIN blocking peptides P-N160 and P-N268, respectively, for 2 h prior to stimulation with T-MV.

Mentions: Next, we investigated how EMMPRIN mediates MV-induced tumor invasion. Although a main function of EMMPRIN is to induce MMP transcription, there was no significant effect of EMMPRIN-positive T-MV on the expression of selected MMPs in the supernatant of MCF-7 or SK-BR-3 cells (Figure 6A, Supplementary Figure S6A–C). Moreover, neither MMP-2 nor MMP-9 could be detected on T-MV, although MV can function as carriers for MMPs as shown by the expression of MMP-9 on MV of human macrophages and platelets (Figure 6B). This suggests that EMMPRIN acts MMP-independently in this context and that the conveyance of MMPs is not the critical discriminator between proinvasive and non-proinvasive MV.Figure 6


Tumor-derived microvesicles mediate human breast cancer invasion through differentially glycosylated EMMPRIN.

Menck K, Scharf C, Bleckmann A, Dyck L, Rost U, Wenzel D, Dhople VM, Siam L, Pukrop T, Binder C, Klemm F - J Mol Cell Biol (2014)

p38 signal transduction partially mediates MV-induced cancer cell invasion. (A) MMP mRNA expression in MCF-7 cells stimulated for 24 h with MV (25 µg/ml) (qRT–PCR, mean ± SD, n = 3). (B) Zymography for MMP-9 in tumor and benign cells (C), as well as their respective MV (SK, SK-BR-3; MΦ, human macrophages; P, platelets). (C) Western blots showing the phosphorylation of p38 and c-jun in MCF-7 cells stimulated with T-MV for the indicated time periods. (D) Analysis of p38 phosphorylation in MCF-7 cells incubated for 1 h with T-MV from EMMPRIN knockdown (shEMP) or non-sense control (ns) cells. (E) Microinvasion assay of MCF-7 cells pretreated with the p38 inhibitor SB-203580 (SB) for 2 h followed by stimulation with T-MV (1 µg/ml) (mean ± SD, n = 3, *P < 0.001). (F) Western blots showing p38 phosphorylation in MCF-7 cells pretreated with two EMMPRIN blocking peptides P-N160 and P-N268, respectively, for 2 h prior to stimulation with T-MV.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401212&req=5

MJU047F6: p38 signal transduction partially mediates MV-induced cancer cell invasion. (A) MMP mRNA expression in MCF-7 cells stimulated for 24 h with MV (25 µg/ml) (qRT–PCR, mean ± SD, n = 3). (B) Zymography for MMP-9 in tumor and benign cells (C), as well as their respective MV (SK, SK-BR-3; MΦ, human macrophages; P, platelets). (C) Western blots showing the phosphorylation of p38 and c-jun in MCF-7 cells stimulated with T-MV for the indicated time periods. (D) Analysis of p38 phosphorylation in MCF-7 cells incubated for 1 h with T-MV from EMMPRIN knockdown (shEMP) or non-sense control (ns) cells. (E) Microinvasion assay of MCF-7 cells pretreated with the p38 inhibitor SB-203580 (SB) for 2 h followed by stimulation with T-MV (1 µg/ml) (mean ± SD, n = 3, *P < 0.001). (F) Western blots showing p38 phosphorylation in MCF-7 cells pretreated with two EMMPRIN blocking peptides P-N160 and P-N268, respectively, for 2 h prior to stimulation with T-MV.
Mentions: Next, we investigated how EMMPRIN mediates MV-induced tumor invasion. Although a main function of EMMPRIN is to induce MMP transcription, there was no significant effect of EMMPRIN-positive T-MV on the expression of selected MMPs in the supernatant of MCF-7 or SK-BR-3 cells (Figure 6A, Supplementary Figure S6A–C). Moreover, neither MMP-2 nor MMP-9 could be detected on T-MV, although MV can function as carriers for MMPs as shown by the expression of MMP-9 on MV of human macrophages and platelets (Figure 6B). This suggests that EMMPRIN acts MMP-independently in this context and that the conveyance of MMPs is not the critical discriminator between proinvasive and non-proinvasive MV.Figure 6

Bottom Line: Uptake of T-MV is essential for the proinvasive effect.Interestingly, the effect of EMMPRIN-bearing MV is not mediated by matrix metalloproteinases but by activation of the p38/MAPK signaling pathway in the tumor cells.In conclusion, T-MV stimulate cancer cell invasion via a direct feedback mechanism dependent on highly glycosylated EMMPRIN.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany.

No MeSH data available.


Related in: MedlinePlus