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Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma.

Massoumi R, Kuphal S, Hellerbrand C, Haas B, Wild P, Spruss T, Pfeifer A, Fässler R, Bosserhoff AK - J. Exp. Med. (2009)

Bottom Line: Rescue of CYLD expression in melanoma cells reduced proliferation and invasion in vitro and tumor growth and metastasis in vivo.Importantly, tumor thickness and progression-free and overall survival inversely correlated with CYLD expression.Our data suggest that Snail1-mediated suppression of CYLD plays a key role in melanoma malignancy.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.

ABSTRACT
High malignancy and early metastasis are hallmarks of melanoma. Here, we report that the transcription factor Snail1 inhibits expression of the tumor suppressor CYLD in melanoma. As a direct consequence of CYLD repression, the protooncogene BCL-3 translocates into the nucleus and activates Cyclin D1 and N-cadherin promoters, resulting in proliferation and invasion of melanoma cells. Rescue of CYLD expression in melanoma cells reduced proliferation and invasion in vitro and tumor growth and metastasis in vivo. Analysis of a tissue microarray with primary melanomas from patients revealed an inverse correlation of Snail1 induction and loss of CYLD expression. Importantly, tumor thickness and progression-free and overall survival inversely correlated with CYLD expression. Our data suggest that Snail1-mediated suppression of CYLD plays a key role in melanoma malignancy.

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CYLD inhibits proliferation and metastasis of melanoma cells in vivo. (A) Growth kinetic of tumors formed by Mel Im control cells (Control) or cells transduced with viral vectors carrying CYLD or GFP after subcutaneous implantation into nude mice (106 cells/mouse). Data represent mean tumor size (± SEM) at different time points. *, P < 0.05 versus both GFP and Control. (B) MIA serum levels in nude mice after i.v. injection of Mel Im control cells (Control) or cells transduced with viral vectors carrying CYLD or GFP (106 cells/mouse; 8–10 mice/group). Data represent mean MIA level (± SEM) 4 wk after injection. (*, P < 0.05 versus both GFP and Control). (C) Immunohistochemical MART1 staining of pulmonary tissue 4 wk after inoculation. Photomicrographs showing representative sections of the lung of mice receiving Mel Im cells transduced with CYLD or GFP. Bar, 200 μm. (D) Number of micrometastatic lesions per one representative cross section of the lungs from each mouse. Data are given as mean ± SEM. *, P < 0.05 compared with control and GFP. Experiments and analysis in A–D have been performed with 8–10 mice/group.
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fig6: CYLD inhibits proliferation and metastasis of melanoma cells in vivo. (A) Growth kinetic of tumors formed by Mel Im control cells (Control) or cells transduced with viral vectors carrying CYLD or GFP after subcutaneous implantation into nude mice (106 cells/mouse). Data represent mean tumor size (± SEM) at different time points. *, P < 0.05 versus both GFP and Control. (B) MIA serum levels in nude mice after i.v. injection of Mel Im control cells (Control) or cells transduced with viral vectors carrying CYLD or GFP (106 cells/mouse; 8–10 mice/group). Data represent mean MIA level (± SEM) 4 wk after injection. (*, P < 0.05 versus both GFP and Control). (C) Immunohistochemical MART1 staining of pulmonary tissue 4 wk after inoculation. Photomicrographs showing representative sections of the lung of mice receiving Mel Im cells transduced with CYLD or GFP. Bar, 200 μm. (D) Number of micrometastatic lesions per one representative cross section of the lungs from each mouse. Data are given as mean ± SEM. *, P < 0.05 compared with control and GFP. Experiments and analysis in A–D have been performed with 8–10 mice/group.

Mentions: To test the effect of CYLD on tumor growth in vivo, we used a murine xenograft model. Mel Im cells stably expressing CYLD were injected subcutaneously into nude mice, revealing significantly impaired growth compared with cells stably expressing GFP or noninfected cells (Fig. 6 A). Similar results were obtained with Mel Juso cells (Fig. S6 A, available at http://www.jem.org/cgi/content/full/jem.20082044/DC1). 14 d after injection, none of the mice from the CYLD group, but 6 out of 10 animals from the GFP and noninfected control groups, developed tumors. After 4 wk, 4 mice from the CYLD group also developed tumors; however, these tumors were significantly smaller (4.3 ± 2.8 vs. 28.6 ± 14.7 mm3 [GFP] and 28.5 ± 10.7 mm3 [noninfected]; Fig. 6 A).


Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma.

Massoumi R, Kuphal S, Hellerbrand C, Haas B, Wild P, Spruss T, Pfeifer A, Fässler R, Bosserhoff AK - J. Exp. Med. (2009)

CYLD inhibits proliferation and metastasis of melanoma cells in vivo. (A) Growth kinetic of tumors formed by Mel Im control cells (Control) or cells transduced with viral vectors carrying CYLD or GFP after subcutaneous implantation into nude mice (106 cells/mouse). Data represent mean tumor size (± SEM) at different time points. *, P < 0.05 versus both GFP and Control. (B) MIA serum levels in nude mice after i.v. injection of Mel Im control cells (Control) or cells transduced with viral vectors carrying CYLD or GFP (106 cells/mouse; 8–10 mice/group). Data represent mean MIA level (± SEM) 4 wk after injection. (*, P < 0.05 versus both GFP and Control). (C) Immunohistochemical MART1 staining of pulmonary tissue 4 wk after inoculation. Photomicrographs showing representative sections of the lung of mice receiving Mel Im cells transduced with CYLD or GFP. Bar, 200 μm. (D) Number of micrometastatic lesions per one representative cross section of the lungs from each mouse. Data are given as mean ± SEM. *, P < 0.05 compared with control and GFP. Experiments and analysis in A–D have been performed with 8–10 mice/group.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2626666&req=5

fig6: CYLD inhibits proliferation and metastasis of melanoma cells in vivo. (A) Growth kinetic of tumors formed by Mel Im control cells (Control) or cells transduced with viral vectors carrying CYLD or GFP after subcutaneous implantation into nude mice (106 cells/mouse). Data represent mean tumor size (± SEM) at different time points. *, P < 0.05 versus both GFP and Control. (B) MIA serum levels in nude mice after i.v. injection of Mel Im control cells (Control) or cells transduced with viral vectors carrying CYLD or GFP (106 cells/mouse; 8–10 mice/group). Data represent mean MIA level (± SEM) 4 wk after injection. (*, P < 0.05 versus both GFP and Control). (C) Immunohistochemical MART1 staining of pulmonary tissue 4 wk after inoculation. Photomicrographs showing representative sections of the lung of mice receiving Mel Im cells transduced with CYLD or GFP. Bar, 200 μm. (D) Number of micrometastatic lesions per one representative cross section of the lungs from each mouse. Data are given as mean ± SEM. *, P < 0.05 compared with control and GFP. Experiments and analysis in A–D have been performed with 8–10 mice/group.
Mentions: To test the effect of CYLD on tumor growth in vivo, we used a murine xenograft model. Mel Im cells stably expressing CYLD were injected subcutaneously into nude mice, revealing significantly impaired growth compared with cells stably expressing GFP or noninfected cells (Fig. 6 A). Similar results were obtained with Mel Juso cells (Fig. S6 A, available at http://www.jem.org/cgi/content/full/jem.20082044/DC1). 14 d after injection, none of the mice from the CYLD group, but 6 out of 10 animals from the GFP and noninfected control groups, developed tumors. After 4 wk, 4 mice from the CYLD group also developed tumors; however, these tumors were significantly smaller (4.3 ± 2.8 vs. 28.6 ± 14.7 mm3 [GFP] and 28.5 ± 10.7 mm3 [noninfected]; Fig. 6 A).

Bottom Line: Rescue of CYLD expression in melanoma cells reduced proliferation and invasion in vitro and tumor growth and metastasis in vivo.Importantly, tumor thickness and progression-free and overall survival inversely correlated with CYLD expression.Our data suggest that Snail1-mediated suppression of CYLD plays a key role in melanoma malignancy.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.

ABSTRACT
High malignancy and early metastasis are hallmarks of melanoma. Here, we report that the transcription factor Snail1 inhibits expression of the tumor suppressor CYLD in melanoma. As a direct consequence of CYLD repression, the protooncogene BCL-3 translocates into the nucleus and activates Cyclin D1 and N-cadherin promoters, resulting in proliferation and invasion of melanoma cells. Rescue of CYLD expression in melanoma cells reduced proliferation and invasion in vitro and tumor growth and metastasis in vivo. Analysis of a tissue microarray with primary melanomas from patients revealed an inverse correlation of Snail1 induction and loss of CYLD expression. Importantly, tumor thickness and progression-free and overall survival inversely correlated with CYLD expression. Our data suggest that Snail1-mediated suppression of CYLD plays a key role in melanoma malignancy.

Show MeSH
Related in: MedlinePlus