Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial intracranial transplantation

Xun Jin, Hee Young Jeon, Kyeung Min Joo, Jun Kyum Kim, Juyoun Jin, Sung Hak Kim, Bong Gu Kang, Samuel Beck, Se Jeong Lee, Joong Kyu Kim, Ae Kyung Park, Woong Yang Park, Yun Jaie Choi, Do Hyun Nam, Hyunggee Kim

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

One of the most detrimental hallmarks of glioblastoma multiforme (GBM) is cellular invasiveness, which is considered a potential cause of tumor recurrence. Infiltrated GBM cells are difficult to completely eradicate surgically and with local therapeutic modalities. Although much effort has focused on understanding the various mechanisms controlling GBM invasiveness, its nature remains poorly understood. In this study, we established highly serial intracranial transplantation. U87R4 cells were highly invasive and displayed stem cell-like properties, as compared to noninvasive but proliferative U87L4 cells. Microarray analysis during serial transplantation revealed that apoptosis-inducing genes (caspase3 and PDCD4) were downregulated whereas several cancer stem cell-relevant genes [Frizzled 4 (FZD4) and CD44] were upregulated in more invasive cells. U87R4 cells were resistant to anticancer drug-induced cell death, partly due to downregulation of caspase3 and PDCD4, and they retained activated Wnt/β-catenin signaling due to upregulation of Frizzled 4, which was sufficient to control neurosphere formation. We also found that FZD4 promoted expression of the epithelial to mesenchymal transition regulator SNAI1, along with acquisition of a mesenchymal phenotype. Taken together, our results argue that Frizzled 4 is a member of the Wnt signaling family that governs both stemness and invasiveness of glioma stem cells, and that it may be a major cause of GBM recurrence and poor prognosis.

Original languageEnglish
Pages (from-to)3066-3075
Number of pages10
JournalCancer Research
Volume71
Issue number8
DOIs
Publication statusPublished - 2011 Apr 15

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Glioma
Glioblastoma
Transplantation
Stem Cells
Down-Regulation
Recurrence
Catenins
Epithelial-Mesenchymal Transition
Neoplastic Stem Cells
Microarray Analysis
Genes
Cell Death
Up-Regulation
Apoptosis
Phenotype
Pharmaceutical Preparations
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial intracranial transplantation. / Jin, Xun; Jeon, Hee Young; Joo, Kyeung Min; Kim, Jun Kyum; Jin, Juyoun; Kim, Sung Hak; Kang, Bong Gu; Beck, Samuel; Lee, Se Jeong; Kim, Joong Kyu; Park, Ae Kyung; Park, Woong Yang; Choi, Yun Jaie; Nam, Do Hyun; Kim, Hyunggee.

In: Cancer Research, Vol. 71, No. 8, 15.04.2011, p. 3066-3075.

Research output: Contribution to journalArticle

Jin, X, Jeon, HY, Joo, KM, Kim, JK, Jin, J, Kim, SH, Kang, BG, Beck, S, Lee, SJ, Kim, JK, Park, AK, Park, WY, Choi, YJ, Nam, DH & Kim, H 2011, 'Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial intracranial transplantation', Cancer Research, vol. 71, no. 8, pp. 3066-3075. https://doi.org/10.1158/0008-5472.CAN-10-1495
Jin, Xun ; Jeon, Hee Young ; Joo, Kyeung Min ; Kim, Jun Kyum ; Jin, Juyoun ; Kim, Sung Hak ; Kang, Bong Gu ; Beck, Samuel ; Lee, Se Jeong ; Kim, Joong Kyu ; Park, Ae Kyung ; Park, Woong Yang ; Choi, Yun Jaie ; Nam, Do Hyun ; Kim, Hyunggee. / Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial intracranial transplantation. In: Cancer Research. 2011 ; Vol. 71, No. 8. pp. 3066-3075.
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