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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.
Afiliación
  • Ramos RI; Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Santa Monica, CA, USA.
  • Bustos MA; Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Santa Monica, CA, USA.
  • Wu J; Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
  • Jones P; Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Santa Monica, CA, USA.
  • Chang SC; Medical Data Research Center, Providence St. Joseph Health Center, Portland, OR, USA.
  • Kiyohara E; Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Santa Monica, CA, USA.
  • Tran K; Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Santa Monica, CA, USA.
  • Zhang X; Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Santa Monica, CA, USA.
  • Stern SL; Department of Biostatistics, JWCI, Santa Monica, CA, USA.
  • Izraely S; Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.
  • Sagi-Assif O; Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.
  • Witz IP; Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.
  • Davies MA; Department of Melanoma Medical Oncology, Systems Biology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Mills GB; Department of Cell Development and Cancer Biology, Oregon Health and Science University (OHSU) Knight Cancer Institute Portland, OR, USA.
  • Kelly DF; Pacific Neuroscience Institute, JWCI, Santa Monica, CA, USA.
  • Irie RF; Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Santa Monica, CA, USA.
  • Hoon DSB; Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Santa Monica, CA, USA.
Mol Oncol ; 14(8): 1760-1778, 2020 08.
Article en En | MEDLINE | ID: mdl-32358995
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Regulación hacia Arriba / Gangliósidos / Melanoma Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Mol Oncol Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Regulación hacia Arriba / Gangliósidos / Melanoma Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Mol Oncol Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos