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)...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-08-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12702 |
| _version_ | 1819194733468057600 |
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| author | Romela Irene Ramos Matias A. Bustos Jinfeng Wu Peter Jones Shu Ching Chang Eiji Kiyohara Kevin Tran Xiaoqing Zhang Stacey L. Stern Sivan Izraely Orit Sagi‐Assif Isaac P. Witz Michael A. Davies Gordon B. Mills Daniel F. Kelly Reiko F. Irie Dave S. B. Hoon |
| author_facet | Romela Irene Ramos Matias A. Bustos Jinfeng Wu Peter Jones Shu Ching Chang Eiji Kiyohara Kevin Tran Xiaoqing Zhang Stacey L. Stern Sivan Izraely Orit Sagi‐Assif Isaac P. Witz Michael A. Davies Gordon B. Mills Daniel F. Kelly Reiko F. Irie Dave S. B. Hoon |
| author_sort | Romela Irene Ramos |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-23T02:01:33Z |
| format | Article |
| id | doaj.art-f837254cc4fc4a5eba73e3a62e629a8c |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-23T02:01:33Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-f837254cc4fc4a5eba73e3a62e629a8c2022-12-21T18:03:59ZengWileyMolecular Oncology1574-78911878-02612020-08-011481760177810.1002/1878-0261.12702Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasisRomela Irene Ramos0Matias A. Bustos1Jinfeng Wu2Peter Jones3Shu Ching Chang4Eiji Kiyohara5Kevin Tran6Xiaoqing Zhang7Stacey L. Stern8Sivan Izraely9Orit Sagi‐Assif10Isaac P. Witz11Michael A. Davies12Gordon B. Mills13Daniel F. Kelly14Reiko F. Irie15Dave S. B. Hoon16Department of Translational Molecular Medicine John Wayne Cancer Institute (JWCI) Santa Monica CA USADepartment of Translational Molecular Medicine John Wayne Cancer Institute (JWCI) Santa Monica CA USADepartment of Dermatology Huashan Hospital Fudan University Shanghai ChinaDepartment of Translational Molecular Medicine John Wayne Cancer Institute (JWCI) Santa Monica CA USAMedical Data Research Center Providence St. Joseph Health Center Portland OR USADepartment of Translational Molecular Medicine John Wayne Cancer Institute (JWCI) Santa Monica CA USADepartment of Translational Molecular Medicine John Wayne Cancer Institute (JWCI) Santa Monica CA USADepartment of Translational Molecular Medicine John Wayne Cancer Institute (JWCI) Santa Monica CA USADepartment of Biostatistics JWCI Santa Monica CA USADepartment of Cell Research and Immunology George S. Wise Faculty of Life Sciences Tel‐Aviv University Tel Aviv IsraelDepartment of Cell Research and Immunology George S. Wise Faculty of Life Sciences Tel‐Aviv University Tel Aviv IsraelDepartment of Cell Research and Immunology George S. Wise Faculty of Life Sciences Tel‐Aviv University Tel Aviv IsraelDepartment of Melanoma Medical Oncology Systems Biology and Translational Molecular Pathology The University of Texas MD Anderson Cancer Center Houston TX USADepartment of Cell Development and Cancer Biology Oregon Health and Science University (OHSU) Knight Cancer Institute Portland OR USAPacific Neuroscience Institute JWCI Santa Monica CA USADepartment of Translational Molecular Medicine John Wayne Cancer Institute (JWCI) Santa Monica CA USADepartment of Translational Molecular Medicine John Wayne Cancer Institute (JWCI) Santa Monica CA USAMelanoma 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.https://doi.org/10.1002/1878-0261.12702gangliosidesGD3lymph nodemelanoma brain metastasisNF‐κBST8SIA1 |
| spellingShingle | Romela Irene Ramos Matias A. Bustos Jinfeng Wu Peter Jones Shu Ching Chang Eiji Kiyohara Kevin Tran Xiaoqing Zhang Stacey L. Stern Sivan Izraely Orit Sagi‐Assif Isaac P. Witz Michael A. Davies Gordon B. Mills Daniel F. Kelly Reiko F. Irie Dave S. B. Hoon Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasis Molecular Oncology gangliosides GD3 lymph node melanoma brain metastasis NF‐κB ST8SIA1 |
| 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 | gangliosides GD3 lymph node melanoma brain metastasis NF‐κB ST8SIA1 |
| url | https://doi.org/10.1002/1878-0261.12702 |
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