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.
Highlights
Neuroblastoma is one of the most common extracranial malignant tumors that develop in children; they arise from neural crest cells and are mostly found in the adrenal medulla or along the sympathetic chain [1]. neuroblastoma exhibits clinical and biological heterogeneity, ranging from rapid progression associated with metastatic spread and poor clinical outcome to occasional, spontaneous, or therapy-induced regression or differentiation into benign ganglioneuroma [2, 3]
Our previous report showed that Neuronal leucine-rich repeat protein-1 (NLRR1) is a direct transcriptional target of MYCN in neuroblastoma, and is associated with cell proliferation and survival [14]
The data suggested that knockdown of NLRR1 suppressed the EGF- and insulin growth factor-1 (IGF-1)–mediated cell proliferation (Fig. 1C)
Summary
Neuroblastoma is one of the most common extracranial malignant tumors that develop in children; they arise from neural crest cells and are mostly found in the adrenal medulla or along the sympathetic chain [1]. neuroblastoma exhibits clinical and biological heterogeneity, ranging from rapid progression associated with metastatic spread and poor clinical outcome to occasional, spontaneous, or therapy-induced regression or differentiation into benign ganglioneuroma [2, 3]. Amplification of the MYCN gene usually distinguishes a subset of neuroblastoma with poor prognosis [1], and recovery of children with high-risk neuroblastoma remains low, providing a compelling reason for better understanding of the molecular mechanisms that can be targeted to treat this disease [5, 6]. The precise mechanism of MYCN regulation and the functional correlation with other proteins in the progression of neuroblastoma are still elusive. We further reported that NLRR1 protein expression is higher in MYCN-amplified primary neuroblastomas than in nonamplified tumors, and that MYCN can transcriptionally upregulate NLRR1 [14]. NLRR family proteins have been considered as cell adhesion or signaling molecules, and mouse NLRR3 functions in EGF-mediated activation of extracellular signal–regulated kinase NLRR family proteins have been considered as cell adhesion or signaling molecules, and mouse NLRR3 functions in EGF-mediated activation of extracellular signal–regulated kinase (ERK; ref. 15)
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