In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5254-5254
Kurzfassung:
We have previously generated neuroblastoma (NB)-prone oligo-capping cDNA libraries from primary neuroblastomas and identified novel important genes. Among those, we selected human neuronal leucine-rich repeat protein (NLRR) family genes for understanding of their functional roles in biology and clinical behavior of NB. In our previous observations, the expression level of NLRR1 mRNA is significantly higher in unfavorable NBs than favorable ones and its high expression is associated with poor clinical outcome, whereas that of NLRR3 is significantly high in favorable NBs in association with good prognosis. These findings suggested that NLRR1 and NLRR3 may have a different and opposite role in regulating cell growth and differentiation in NB. On the other hand, NLRR2 is similarly expressed in both subsets of NB. However, their real function in NB still remains elusive. Our present studies showed that cell proliferation was increased by overexpression of NLRR1 with enhanced EGF and IGF signals. NLRR1 proteins localized in cholesterol-rich lipid raft microdomain of cellular membrane and its expression altered the membrane distribution of EGFR and IGF-1R. Treatment of methyl-β-cyclodextrin to deplete membrane cholesterol and disrupt lipid rafts diminished the effect of NLRR1 on EGFR, suggesting that NLRR1 accelerates growth signaling pathway through lipid raft microdomains. Transcriptional study revealed that stimulation of EGF and IGF signaling enhanced the transcriptional activity of MYCN gene and MYCN in turn transactivates NLRR1 transcription, suggesting that NLRR1 and MYCN, both of which are poor prognostic factors in NBs, form a positive feedback loop via EGFR and IGF-1R. On the contrary, we observed opposite results in the study on NLRR3. The transcription was negatively regulated by MYCN with Max and Miz-1. Interestingly, enforced expression of NLRR3 induced neuronal differentiation and siRNA-mediated knockdown of NLRR3 reduced retinoic acid-induced neuronal differentiation in NB cells. Quantitative PCR also showed the inverse relationship between NLRR3 and MYCN in primary NB tissues. The combination of low NLRR3 and low Miz-1 expression or that of low NLRR3 and high MYCN expression was significantly associated with a poor prognosis. The current study on NLRR2 so far indicated its involvement in endoplasmic reticulum-stress response. Collectively, our results suggest that the transcriptional regulation varies between NLRR family genes and they play different roles in cell fate decision and contribute to the clinical outcome of NBs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5254.
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-5254
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2010
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
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