Fak is a critical regulator of neuroblastoma liver metastasis

Sora Lee, Jingbo Qiao, Pritha Paul, Kathleen L. O'connor, Mark B. Evers, Dai H. Chung

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Neuroblastomas express increased levels of gastrin-releasing peptide receptor (GRP-R). However, the exact molecular mechanisms involved in GRP-R-mediated cell signaling in neuroblastoma growth and metastasis are unknown. Here, we report that focal adhesion kinase (FAK), as a critical downstream target of GRP-R, is an important regulator of neuroblastoma tumorigenicity. We found that FAK expression correlates with GRP-R expression in human neuroblastoma sections and cell lines. GRP-R overexpression in SK-N-SH cells increased FAK, integrin α3 and β1 expressions and cell migration. These cells demonstrated flatter cell morphology with broad lamellae, in which intense FAK expression was localized to the leading edges of lamellipodia. Interestingly, FAK activation was, in part, dependent on integrin α3 and β1 expression. Conversely, GRP-R silencing decreased FAK as well as Mycn levels in BE(2)-C cells, which displayed a denser cellular morphology. Importantly, rescue experiments in GRP-R silenced BE(2)-C cells showed FAK overexpression significantly enhanced cell viability and soft agar colony formation; similarly, FAK overexpression in SK-N-SH cells also resulted in increased cell growth. These effects were reversed in FAK silenced BE(2)-C cells in vitro as well as in vivo. Moreover, we evaluated the effect of FAK inhibition in vivo. FAK inhibitor (Y15) suppressed GRP-induced neuroblastoma growth and metastasis. Our results indicate that FAK is a critical downstream regulator of GRP-R, which mediates tumorigenesis and metastasis in neuroblastoma.

Original languageEnglish (US)
Pages (from-to)1576-1587
Number of pages12
JournalOncotarget
Volume3
Issue number12
DOIs
StatePublished - Dec 2012
Externally publishedYes

Fingerprint

Focal Adhesion Protein-Tyrosine Kinases
Neuroblastoma
Bombesin Receptors
Neoplasm Metastasis
Liver
Integrins
Growth
Pseudopodia
Agar
Cell Movement
Cell Survival
Carcinogenesis

Keywords

  • FAK
  • GRP-R
  • Malignant transformation
  • Metastasis
  • Neuroblastoma

ASJC Scopus subject areas

  • Oncology

Cite this

Fak is a critical regulator of neuroblastoma liver metastasis. / Lee, Sora; Qiao, Jingbo; Paul, Pritha; O'connor, Kathleen L.; Evers, Mark B.; Chung, Dai H.

In: Oncotarget, Vol. 3, No. 12, 12.2012, p. 1576-1587.

Research output: Contribution to journalArticle

Lee, Sora ; Qiao, Jingbo ; Paul, Pritha ; O'connor, Kathleen L. ; Evers, Mark B. ; Chung, Dai H. / Fak is a critical regulator of neuroblastoma liver metastasis. In: Oncotarget. 2012 ; Vol. 3, No. 12. pp. 1576-1587.
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