Hexokinase 2 is a determinant of neuroblastoma metastasis

Liat Edry Botzer, Shelly Maman, Orit Sagi-Assif, Tsipi Meshel, Ido Nevo, Ilana Yron, Isaac P. Witz

Research output: Contribution to journalArticlepeer-review

Abstract

Background:Intersecting a genome-wide expression profile of metastatic and nonmetastatic human neuroblastoma xenograft variants with expression profiles of tumours from stage 1 and 4 neuroblastoma patients, we previously characterised hexokinase 2 (HK2) as a gene whose expression was upregulated in both metastatic neuroblastoma variants and tumours from stage 4 neuroblastoma patients.Methods:Local and metastatic neuroblastoma cell variants as well as metastatic neuroblastoma cells genetically manipulated to downregulate the expression of HK2 were utilised for in vitro and in vivo examinations of the involvement of HK2 in neuroblastoma.Results:Hexokinase 2 expression and its activity levels were increased in neuroblastoma metastatic variants as compared with the local variants. The upregulation of HK2 confers upon the metastatic cells high resistance to the antiproliferative effect of the HK2 inhibitor 3-BrPa and to the chemotherapy agent Deferoxamine. The inhibition of HK2 transcript lowered the proliferation and motility of sh-HK2 cells as compared with sh-control cells. Mice that were inoculated with sh-HK2 cells had a lower incidence of local tumours, smaller tumour volumes and a diminished load of lung metastasis compared with mice inoculated with sh-control cells.Conclusions:Hexokinase 2 plays a significant role in shaping the malignant phenotype of neuroblastoma and influences the progression of this disease.

Original languageEnglish
Pages (from-to)759-766
Number of pages8
JournalBritish Journal of Cancer
Volume114
Issue number7
DOIs
StatePublished - 1 Mar 2016

Keywords

  • HIF-1α
  • Warburg effect
  • hexokinase 2
  • metastasis
  • neuroblastoma

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