Biological effects of TrkA and TrkB receptor signaling in neuroblastoma

Schramm, Alexander; Schulte, Johannes H.; Astrahantseff, Kathy; Apostolov, Ognjan; Limpt, Vera van; Sieverts, Hauke; Kuhfittig-Kulle, Steffi; Pfeiffer, Petra; Versteeg, Rogier; Eggert, Angelika

doi:10.1016/j.canlet.2005.02.051

Cited by 111 publications

(101 citation statements)

References 71 publications

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“…On the other hand, the expressions of the neurotrophin receptors TrkA (Nakagawara et al, 1993) and TrkC (Yamashiro et al, 1997) are found in favorable NBs, with high expression of TrkA being accompanied by massive changes in the transcriptome of NBs (Schramm et al, 2005b). This biological diversity between TrkA and TrkB expression could also be verified in vitro (Lucarelli et al, 1997;Schramm et al, 2005a). Taken together, the identification of effector targets differentially regulated between TrkA-and TrkB-expressing NBs could serve as drug targets for NB treatment.…”

Section: Discussionmentioning

confidence: 98%

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

et al. 2009

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Expression of Trk receptors is an important prognostic factor in neuroblastoma (NB) and other cancers. TrkB and its ligand brain-derived neurotrophic factor (BDNF) are preferentially expressed in NB with poor prognosis, conferring invasive and metastatic potential to the tumor cells as well as enhancing therapy resistance. Galectin-1 (Gal-1) has emerged as an interesting cancer target, as it is involved in modulating cell proliferation, cell death and cell migration, all of which are linked to cancer initiation and progression. We previously identified Gal-1 mRNA to be upregulated in patients with aggressive, relapsing NB and found that Gal-1 protein was upregulated in human SY5Y NB cells on activation of ectopically expressed TrkB (SY5Y-TrkB), but not TrkA (SY5Y-TrkA). Here, we report that Gal-1 mRNA levels positively correlated with TrkB expression and anticorrelated with TrkA expression in a cohort of 102 primary NB. Immunohistochemical analyses of 92 primary NB specimens revealed high Gal-1 expression in stromal septae and in neuroblasts. BDNF-mediated activation of TrkB enhanced invasiveness and migration in vitro, which could be impaired by transient transfection using Gal-1-specific siRNA or a neutralizing antibody directed against Gal-1. The addition of recombinant Gal-1 (rGal-1) in the absence of BDNF partially restored migration and invasive capacity. Using the Trk inhibitor K252a, we could show that the upregulation of Gal-1 protein strictly depended on activated TrkB. Our data suggest that targeting Gal-1 might be a promising strategy for the treatment of aggressive NB.

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Section: Discussionmentioning

confidence: 98%

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

et al. 2009

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“…This enhanced growth is in part induced by aberrant expression of neurotrophic factors. Among these, brain-derived neurotrophic factor (BDNF) and its cognate receptor NTRK2/TrkB have been shown to correlate with poor prognosis and resistance to chemotherapeutic agents (Li et al, 2005;Schramm et al, 2005). BDNF/TrkB induces survival signaling via the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) pathway.…”

Section: Introductionmentioning

confidence: 99%

Repression of BIRC5/Survivin by FOXO3/FKHRL1 Sensitizes Human Neuroblastoma Cells to DNA Damage-induced Apoptosis

Obexer

Hagenbuchner

Unterkircher³

et al. 2009

MBoC

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“…High expression of TrkA is associated with favorable outcome in neuroblastoma (10,25,26). Although there were several prognostic factors of favorable outcomes in neuroblastomas, hypermehtylation level of the 5'-end of ZNF206-exon 5 CpGi was significantly correlated with ZFP206 expression and favorable outcome suggesting that ZFP206 and the DNA methylation could be prognostic biomarkers in neuroblastoma.…”

Section: Discussionmentioning

confidence: 94%

DNA hypomethylation at the ZNF206-exon 5 CpG island associated with neuronal differentiation in mice and development of neuroblastoma in humans

Kawashima

Sugito²,

Yoshizawa³

et al. 2011

Int J Oncol

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Abstract. Differentiation of human neuroblastoma recapitulates neural crest development. In our whole genome DNA methylation screening of tissue-specific differentially methylated regions (T-DMRs) and developmental stage specific differentially methylated regions (DS-DMRs) we reported that the exon 5 CpG island (CpGi) of Zfp206 (human: ZNF206), which was required to maintain embryonic stem cells in a pluripotent state, was one of potent brain and testis-specific T-DMRs in mice. In this study methylation level of the CpG sites at Zfp206-exon 5 CpGi in mouse brain samples at three different developmental stages (15-day-old embryo; E15, new born; NB, 12-week adult; AD) were quantitatively analyzed and it was identified that Zfp206-exon 5 CpGi was the DS-DMRs in mouse brain. In AD brains, Zfp206-exon 5 CpGi was significantly hypomethylated and Zfp206 expression was repressed, compared with E15 and NB brains. Hence, mehtylation level of human 5'-end of CpGi at ZNF206-exon 5, which is homologous CpGi to mice, was analyzed in neuroblastomas. Although all four adrenal samples showed complete methylation at the homologous region, we found the hypomethylation in 7 out of 26 neuroblastomas and a significant association between the hypomethylation and poor prognosis. In neuroblastoma cell lines and specimens, the hypomethylation was also associated with ZNF206 expression. These data indicated that the changes in DNA methylation levels at the Zfp206-exon 5 might be one of the important factors during neuronal development in mice and that the hypomethylation of the homologous region induced ZNF206 expression in humans and was associated with human neuroblastomagenesis. Even though the function of ZNF206 and its expression regulation in neuroblastoma remain elusive, ZNF206 might be a candidate differentiation suppressor and prognosis marker in neuroblastoma. IntroductionEpigenetic programing predetermines the developmental program and provides necessary direction for the multitude of changes that are required to proceed from a fertilized oocyte to a fully developed adult animal (1). It has been suggested that epigenetic changes are associated with development and differentiation. DNA methylation is one of the epigenetic factors and plays an important role in the diverse genomic process, such as gene regulation, chromosomal stability, parental imprinting and X-inactivation (2). Recent genome-wide DNA methylation searches indicate that 4-17% of CpG sites are different in methylation among tissues and developmental processes (3,4). Tissue-specific differentially methylated regions (T-DMRs) and developmental-specific differentially methylated regions (DS-DMRs) are suggested to play important roles in development and differentiation (5). Therefore, disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation (6). For example, Hox genes are involved in determining anterior-posterior embryonic pattern and govern DNA hypomethylation at the ZNF206-exon 5 CpG island associated with neuronal ...

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Biological effects of TrkA and TrkB receptor signaling in neuroblastoma

Cited by 111 publications

References 71 publications

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

Repression of BIRC5/Survivin by FOXO3/FKHRL1 Sensitizes Human Neuroblastoma Cells to DNA Damage-induced Apoptosis

DNA hypomethylation at the ZNF206-exon 5 CpG island associated with neuronal differentiation in mice and development of neuroblastoma in humans

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