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

Mol Oncol. 2020 Aug;14(8):1760-1778. doi: 10.1002/1878-0261.12702. Epub 2020 Jun 5.

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.

Keywords: GD3; NF-κB; ST8SIA1; gangliosides; lymph node; melanoma brain metastasis.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Proliferation / drug effects
  • Female
  • Flavonoids / pharmacology
  • Gangliosides / metabolism*
  • Humans
  • Lymphatic Metastasis / pathology
  • Male
  • Melanoma / pathology*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Multivariate Analysis
  • Phenotype
  • Prognosis
  • Proportional Hazards Models
  • Sialyltransferases / metabolism
  • Tumor Stem Cell Assay
  • Up-Regulation* / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Flavonoids
  • Gangliosides
  • ganglioside, GD3
  • Sialyltransferases
  • alpha-N-acetylneuraminate alpha-2,8-sialyltransferase
  • icaritin