FAK is a critical regulator of neuroblastoma liver metastasis
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Sora Lee1,2, Jingbo Qiao1, Pritha Paul1,2, Kathleen L. O’Connor3,4, B. Mark Evers3,4, Dai H. Chung1,2
1 Departments of Pediatric Surgery, Vanderbilt University Medical Center1, Nashville, TN
2 Cancer Biology, Vanderbilt University Medical Center1, Nashville, TN
3 Department of Surgery, University of Kentucky, Lexington, KY
4 Markey Cancer Center, University of Kentucky, Lexington, KY
Dai H. Chung, email:
Keywords: GRP-R, FAK, malignant transformation, metastasis, neuroblastoma
Received: November 01, 2012, Accepted: November 14, 2012, Published: November 16, 2012
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.
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