Neuron navigator 3 alterations in nervous system tumors associate with tumor malignancy grade and prognosis

Abstract

Copy number changes or reduced expression of the Neuron navigator 3 (NAV3) gene occurs in neuroblastomas and malignancies of epithelial or lymphoid origin. To elucidate whether NAV3 has a role in the tumorigenesis of nervous system tumors in general, we studied central and peripheral nervous system tumors for NAV3 copy number changes. In search for common tumorigenic denominators, we analyzed 113 central and peripheral nervous system tumors, including glial tumors (grades I-IV gliomas), medulloblastomas, and neuroblastomas. NAV3 copy number changes were studied by fluorescence in situ hybridization and correlated to survival analyses. To identify target genes of NAV3 deletion, NAV3 was silenced by siRNA in glioblastoma cell lines and gene expression profiles were analyzed by Agilent 4×44k dual-color microarrays. Selected upregulations were confirmed by immunohistochemistry and quantitative polymerase chain reaction. We found NAV3 amplifications to dominate in neuronally differentiated tumors, whereas glial tumors showed almost equal proportions of NAV3 deletion and amplification. However, Grade IV gliomas had more frequent NAV3 deletions than grades I-III gliomas. Silencing of NAV3 in glioma cell lines led to the upregulation of receptor genes associated with gonadotropin-releasing hormone and Jak-Stat signaling pathways. Kaplan-Meier analysis of the entire clinical tumor material showed association between NAV3 amplifications and favorable prognosis, as well as NAV3 deletions and unfavorable prognosis. With Cox regression model, a hazard ratio of 0.51 was observed for NAV3 amplifications and 1.36 for NAV3 deletions. We conclude that NAV3 may be a potential new prognostic biomarker and a potential therapeutic target.

MiR-21 promoted proliferation and migration in hepatocellular carcinoma through negative regulation of Navigator-3

“…In our study, our results showed that knock-down of NAV-3 can promote both the proliferation and migration of HCC cells, which was in agreement with findings by Cohen-Dvashi H and colleagues [11] in breast cancer. In HCC tissues, we found that lower expression of NAV-3 was significantly associated with poor prognosis, which was also consistent with conclusions given by Carlsson E et al [15] in nervous system tumors and Cohen-Dvashi H et al [11] in breast cancer that NAV-3 may be a potential new prognostic biomarker, despite the limited cases of HCC we've employed and enrolled. As for the specific miRNAs that could M A N U S C R I P T…”

“…No more study mentioned any miRNA that could potentially regulate NAV-3 in diseases in any form. Consequently, based on the previous studies in cancers [10,11,15], it fairly can be suggested that NAV-3 may play an anti-oncogenic role in cancers, which was backed up by our current study in HCC.…”

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

“…Since all mutations are predicted to affect HTRA1 protein stability (Figure 5), we suggest that the observed variants may act as loss-of-function mutations that enhance invasion or metastasis of tumor cells. Four mutations were found in two functionally similar genes NAV1 and NAV3 involved in neuronal development and cell migration [22]. Of note NAV3 deletions have been associated with poor prognosis in nervous system tumors including neuroblastoma [22].…”

Risk of false positive genetic associations in complex traits with underlying population structure: A case study

“…STY4 encodes for synaptotagmin 4, a vesicle protein implicated in neurotransmitter release from neural and neuroendocrine tissues (Thomas and Elferink, 1998). The SNP at ECA28:5813320 is located within intron 11–12 of NAV3 , a gene belonging to the neuron navigator family and has been implicated in cancer progression (Carlsson et al, 2013). …”

“…We have previously excluded TTPA as a candidate gene for NAD/EDM (Finno et al, 2013). The SNP at ECA28:5813320 is located within intron 11–12 of NAV3 , a gene that has primarily been associated with central and peripheral nervous system tumors (Carlsson et al, 2013). Although there is no evidence that NAV3 is involved in synaptic transmission or vitamin E and lipid transport, this particular gene may warrant further investigation in NAD/EDM.…”