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Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasis

Melanoma metastasis to the brain is one of the most frequent extracranial brain tumors. Cell surface gangliosides are elevated in melanoma metastasis; however, the metabolic regulatory mechanisms that govern these specific changes are poorly understood in melanoma particularly brain metastases (MBM)...

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Autores principales: Ramos, Romela Irene, Bustos, Matias A., Wu, Jinfeng, Jones, Peter, Chang, Shu Ching, Kiyohara, Eiji, Tran, Kevin, Zhang, Xiaoqing, Stern, Stacey L., Izraely, Sivan, Sagi‐Assif, Orit, Witz, Isaac P., Davies, Michael A., Mills, Gordon B., Kelly, Daniel F., Irie, Reiko F., Hoon, Dave S. B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400791/
https://www.ncbi.nlm.nih.gov/pubmed/32358995
http://dx.doi.org/10.1002/1878-0261.12702
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author Ramos, Romela Irene
Bustos, Matias A.
Wu, Jinfeng
Jones, Peter
Chang, Shu Ching
Kiyohara, Eiji
Tran, Kevin
Zhang, Xiaoqing
Stern, Stacey L.
Izraely, Sivan
Sagi‐Assif, Orit
Witz, Isaac P.
Davies, Michael A.
Mills, Gordon B.
Kelly, Daniel F.
Irie, Reiko F.
Hoon, Dave S. B.
author_facet Ramos, Romela Irene
Bustos, Matias A.
Wu, Jinfeng
Jones, Peter
Chang, Shu Ching
Kiyohara, Eiji
Tran, Kevin
Zhang, Xiaoqing
Stern, Stacey L.
Izraely, Sivan
Sagi‐Assif, Orit
Witz, Isaac P.
Davies, Michael A.
Mills, Gordon B.
Kelly, Daniel F.
Irie, Reiko F.
Hoon, Dave S. B.
author_sort Ramos, Romela Irene
collection PubMed
description Melanoma metastasis to the brain is one of the most frequent extracranial brain tumors. Cell surface gangliosides are elevated in melanoma metastasis; however, the metabolic regulatory mechanisms that govern these specific changes are poorly understood in melanoma particularly brain metastases (MBM) development. We found ganglioside GD3 levels significantly upregulated in MBM compared to lymph node metastasis (LNM) but not for other melanoma gangliosides. Moreover, we demonstrated an upregulation of ST8SIA1 (GD3 synthase) as melanoma progresses from melanocytes to MBM cells. Using RNA‐ISH on FFPE specimens, we evaluated ST8SIA1 expression in primary melanomas (PRM) (n = 23), LNM and visceral metastasis (n = 45), and MBM (n = 39). ST8SIA1 was significantly enhanced in MBM compared to all other specimens. ST8SIA1 expression was assessed in clinically well‐annotated melanoma patients from multicenters with AJCC stage III B‐D LNM (n = 58) with 14‐year follow‐up. High ST8SIA1 expression was significantly associated with poor overall survival (HR = 3.24; 95% CI, 1.19–8.86, P = 0.02). In a nude mouse human xenograft melanoma brain metastasis model, MBM variants had higher ST8SIA1 expression than their respective cutaneous melanoma variants. Elevated ST8SIA1 expression enhances levels of cell surface GD3, a phenotype that favors MBM development, hence associated with very poor prognosis. Functional assays demonstrated that ST8SIA1 overexpression enhanced cell proliferation and colony formation, whereby ST8SIA1 knockdown had opposite effects. Icaritin a plant‐derived phytoestrogen treatment significantly inhibited cell growth in high GD3‐positive MBM cells through targeting the canonical NFκB pathway. The study demonstrates GD3 phenotype associates with melanoma progression and poor outcome.
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spelling pubmed-74007912020-08-06 Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasis Ramos, Romela Irene Bustos, Matias A. Wu, Jinfeng Jones, Peter Chang, Shu Ching Kiyohara, Eiji Tran, Kevin Zhang, Xiaoqing Stern, Stacey L. Izraely, Sivan Sagi‐Assif, Orit Witz, Isaac P. Davies, Michael A. Mills, Gordon B. Kelly, Daniel F. Irie, Reiko F. Hoon, Dave S. B. Mol Oncol Research Articles Melanoma metastasis to the brain is one of the most frequent extracranial brain tumors. Cell surface gangliosides are elevated in melanoma metastasis; however, the metabolic regulatory mechanisms that govern these specific changes are poorly understood in melanoma particularly brain metastases (MBM) development. We found ganglioside GD3 levels significantly upregulated in MBM compared to lymph node metastasis (LNM) but not for other melanoma gangliosides. Moreover, we demonstrated an upregulation of ST8SIA1 (GD3 synthase) as melanoma progresses from melanocytes to MBM cells. Using RNA‐ISH on FFPE specimens, we evaluated ST8SIA1 expression in primary melanomas (PRM) (n = 23), LNM and visceral metastasis (n = 45), and MBM (n = 39). ST8SIA1 was significantly enhanced in MBM compared to all other specimens. ST8SIA1 expression was assessed in clinically well‐annotated melanoma patients from multicenters with AJCC stage III B‐D LNM (n = 58) with 14‐year follow‐up. High ST8SIA1 expression was significantly associated with poor overall survival (HR = 3.24; 95% CI, 1.19–8.86, P = 0.02). In a nude mouse human xenograft melanoma brain metastasis model, MBM variants had higher ST8SIA1 expression than their respective cutaneous melanoma variants. Elevated ST8SIA1 expression enhances levels of cell surface GD3, a phenotype that favors MBM development, hence associated with very poor prognosis. Functional assays demonstrated that ST8SIA1 overexpression enhanced cell proliferation and colony formation, whereby ST8SIA1 knockdown had opposite effects. Icaritin a plant‐derived phytoestrogen treatment significantly inhibited cell growth in high GD3‐positive MBM cells through targeting the canonical NFκB pathway. The study demonstrates GD3 phenotype associates with melanoma progression and poor outcome. John Wiley and Sons Inc. 2020-06-05 2020-08 /pmc/articles/PMC7400791/ /pubmed/32358995 http://dx.doi.org/10.1002/1878-0261.12702 Text en © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Ramos, Romela Irene
Bustos, Matias A.
Wu, Jinfeng
Jones, Peter
Chang, Shu Ching
Kiyohara, Eiji
Tran, Kevin
Zhang, Xiaoqing
Stern, Stacey L.
Izraely, Sivan
Sagi‐Assif, Orit
Witz, Isaac P.
Davies, Michael A.
Mills, Gordon B.
Kelly, Daniel F.
Irie, Reiko F.
Hoon, Dave S. B.
Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasis
title Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasis
title_full Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasis
title_fullStr Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasis
title_full_unstemmed Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasis
title_short Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasis
title_sort upregulation of cell surface gd3 ganglioside phenotype is associated with human melanoma brain metastasis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400791/
https://www.ncbi.nlm.nih.gov/pubmed/32358995
http://dx.doi.org/10.1002/1878-0261.12702
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