title: NLRR1 enhances EGF-mediated MYCN induction in neuroblastoma and accelerates tumor growth in vivo.
abstract: Neuronal leucine-rich repeat protein-1 (NLRR1), a type-1 transmembrane protein highly expressed in unfavorable neuroblastoma, is a target gene of MYCN that is predominately expressed in primary neuroblastomas with MYCN amplification. However, the precise biological role of NLRR1 in cell proliferation and tumor progression remains unknown. To investigate its functional importance, we examined the role of NLRR1 in EGF and insulin growth factor-1 (IGF-1)-mediated cell viability. We found that NLRR1 positively regulated cell proliferation through activation of extracellular signal-regulated kinase mediated by EGF and IGF-1. Interestingly, EGF stimulation induced endogenous MYCN expression through Sp1 recruitment to the MYCN promoter region, which was accelerated in NLRR1-expressing cells. The Sp1-binding site was identified on the promoter region for MYCN induction, and phosphorylation of Sp1 was important for EGF-mediated MYCN regulation. In vivo studies confirmed the proliferation-promoting activity of NLRR1 and established an association between NLRR1 expression and poor prognosis in neuroblastoma. Together, our findings indicate that NLRR1 plays an important role in the development of neuroblastoma and therefore may represent an attractive therapeutic target for cancer treatment.
authors: Divisions of Biochemistry & Innovative Cancer Therapeutics and Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan.
authors: Shamim
authors: S
authors: Hossain
authors: Atsushi
authors: A
authors: Takatori
authors: Yohko
authors: Y
authors: Nakamura
authors: Yusuke
authors: Y
authors: Suenaga
authors: Takehiko
authors: T
authors: Kamijo
authors: Akira
authors: A
authors: Nakagawara
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000071447:N-Myc Proto-Oncogene Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C494421:LRRN1 protein, human; C459801:MYCN protein, human; D008565:Membrane Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016329:Sp1 Transcription Factor; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D048049:Extracellular Signal-Regulated MAP Kinases