1. Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasis
- Author
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Jinfeng Wu, Shu Ching Chang, Eiji Kiyohara, Reiko F. Irie, Isaac P. Witz, Daniel F. Kelly, Gordon B. Mills, Orit Sagi-Assif, Stacey L. Stern, Matias A. Bustos, Kevin Tran, Sivan Izraely, Peter C. Jones, Michael A. Davies, Romela Irene Ramos, Dave S.B. Hoon, and Xiaoqing Zhang
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Cell ,Metastasis ,0302 clinical medicine ,Nude mouse ,Melanoma ,Research Articles ,Tumor Stem Cell Assay ,Mice, Inbred BALB C ,biology ,Brain Neoplasms ,General Medicine ,Middle Aged ,lymph node ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,gangliosides ,Up-Regulation ,medicine.anatomical_structure ,Phenotype ,Oncology ,030220 oncology & carcinogenesis ,Lymphatic Metastasis ,Molecular Medicine ,Female ,Research Article ,Mice, Nude ,lcsh:RC254-282 ,03 medical and health sciences ,melanoma brain metastasis ,Cell Line, Tumor ,Genetics ,medicine ,Ganglioside GD3 ,Animals ,Humans ,Cell Proliferation ,Proportional Hazards Models ,Flavonoids ,Cell growth ,business.industry ,Cell Membrane ,NF‐κB ,GD3 ,medicine.disease ,biology.organism_classification ,Xenograft Model Antitumor Assays ,Sialyltransferases ,030104 developmental biology ,Cutaneous melanoma ,Multivariate Analysis ,Cancer research ,business ,ST8SIA1 ,Brain metastasis - Abstract
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., We demonstrated the upregulation of a ganglioside synthase, ST8SIA1 and GD3 expression in MBM, which can be suppressed by icaritin treatment. Icaritin inhibits NFκB‐mediated activation of ST8SIA1 by downregulating p50. These findings suggest that ST8SIA1 is a significant factor and potential target to MBM.
- Published
- 2020