Gene Summary

Gene:NBL1; NBL1, DAN family BMP antagonist
Aliases: NB, DAN, NO3, DAND1, D1S1733E
Summary:This gene product is the founding member of the evolutionarily conserved CAN (Cerberus and DAN) family of proteins, which contain a domain resembling the CTCK (C-terminal cystine knot-like) motif found in a number of signaling molecules. These proteins are secreted, and act as BMP (bone morphogenetic protein) antagonists by binding to BMPs and preventing them from interacting with their receptors. They may thus play an important role during growth and development. Alternatively spliced transcript variants have been identified for this gene. Read-through transcripts between this locus and the upstream mitochondrial inner membrane organizing system 1 gene (GeneID 440574) have been observed. [provided by RefSeq, May 2013]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:neuroblastoma suppressor of tumorigenicity 1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (9)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Microtubule-Associated Proteins
  • Amino Acid Sequence
  • Seminal Plasma Proteins
  • Adolescents
  • Biomarkers, Tumor
  • Nerve Tissue Proteins
  • Cancer DNA
  • Genetic Markers
  • Young Adult
  • Neuroblastoma
  • Tumor Suppressor Proteins
  • Tissue Distribution
  • Up-Regulation
  • Down-Regulation
  • Polymerase Chain Reaction
  • Protein Biosynthesis
  • Tumor Suppressor Gene
  • Sequence Homology
  • Cloning, Molecular
  • Cultured Cells
  • NBL1
  • Restriction Mapping
  • DNA, Complementary
  • Utrophin
  • Vincristine
  • Molecular Sequence Data
  • Cancer Gene Expression Regulation
  • Messenger RNA
  • Neoplastic Cell Transformation
  • Survivin
  • Gene Expression
  • Transcription
  • Tobacco
  • Base Sequence
  • Proteins
  • Chromosome Mapping
  • Chromosome 1
  • Gene Expression Profiling
  • Prostate Cancer
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NBL1 (cancer-related)

Hu Q, Ye Y, Chan LC, et al.
Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.
Nat Immunol. 2019; 20(7):835-851 [PubMed] Article available free on PMC after 03/12/2019 Related Publications
How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.

Liu J, Wang T, Creighton CJ, et al.
Nat Commun. 2019; 10(1):2148 [PubMed] Article available free on PMC after 03/12/2019 Related Publications
Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.

Dong H, Adams NM, Xu Y, et al.
The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc.
Nat Immunol. 2019; 20(7):865-878 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
Natural killer (NK) cells are critical mediators of host immunity to pathogens. Here, we demonstrate that the endoplasmic reticulum stress sensor inositol-requiring enzyme 1 (IRE1α) and its substrate transcription factor X-box-binding protein 1 (XBP1) drive NK cell responses against viral infection and tumors in vivo. IRE1α-XBP1 were essential for expansion of activated mouse and human NK cells and are situated downstream of the mammalian target of rapamycin signaling pathway. Transcriptome and chromatin immunoprecipitation analysis revealed c-Myc as a new and direct downstream target of XBP1 for regulation of NK cell proliferation. Genetic ablation or pharmaceutical blockade of IRE1α downregulated c-Myc, and NK cells with c-Myc haploinsufficency phenocopied IRE1α-XBP1 deficiency. c-Myc overexpression largely rescued the proliferation defect in IRE1α

Jiang D, Wang X, Wang Y, et al.
Mutation in BRAF and SMAD4 associated with resistance to neoadjuvant chemoradiation therapy in locally advanced rectal cancer.
Virchows Arch. 2019; 475(1):39-47 [PubMed] Related Publications
Our study was done in order to identify novel molecular markers to predict which locally advanced rectal cancers (LARCs) might be resistant to neoadjuvant chemoradiotherapy (nCRT). Seventy-four patients with LARCs treated with nCRT were collected. Pathological evaluation after nCRT was performed according to the tumor regression grading (TRG) system. Next-generation sequencing kit including 279 exons of 59 genes was performed on Illumina Miseq Platform. Sanger sequencing was performed to confirm some mutations. Four of the tumors (4/74, 5.4%) had BRAF mutation, which presented in one TRG 2 tumor and three TRG 3 tumors but was not observed in TRG 0-1 tumors. Higher mutational frequency of BRAF gene in TRG 3 tumors (3/12, 25%) was found in comparison with the TRG 0-2 tumors (1/62, 1.6%; p = 0.012). Eight tumors (8/74, 10.8%) harbored SMAD4 mutations, which was mutated across all TRG groups. However, SMAD4 mutated more in TRG 3 tumors (4/12, 33.3%) compared with that in TRG 0-2 tumors (4/62, 6.5%; p = 0.020). The patients with BRAF-mutated LARCs had shorter progression-free survival (PFS) (p = 0.045) and shorter overall survival (OS) (p = 0.000) than the BRAF wild-type (WT) ones. The patients with SMAD4-mutated tumors had shorter PFS than the WT cases (p = 0.008). BRAF and SMAD4 genetic mutations might be important molecular markers to predict resistance to nCRT and poor prognosis in LARCs. More cases are needed to confirm these findings in the near future.

Kim SL, Choi HS, Kim JH, et al.
Dihydrotanshinone-Induced NOX5 Activation Inhibits Breast Cancer Stem Cell through the ROS/Stat3 Signaling Pathway.
Oxid Med Cell Longev. 2019; 2019:9296439 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
Cancer stem cells (CSCs) are known to mediate metastasis and recurrence and are therefore a promising therapeutic target. In this study, we found that dihydrotanshinone (DHTS) inhibits CSC formation. DHTS inhibited mammosphere formation in a dose-dependent manner and showed significant tumor growth inhibition in a xenograft model. This compound reduced the CD44

Zhou Y, Gerrard DL, Wang J, et al.
Temporal dynamic reorganization of 3D chromatin architecture in hormone-induced breast cancer and endocrine resistance.
Nat Commun. 2019; 10(1):1522 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
Recent studies have demonstrated that chromatin architecture is linked to the progression of cancers. However, the roles of 3D structure and its dynamics in hormone-dependent breast cancer and endocrine resistance are largely unknown. Here we report the dynamics of 3D chromatin structure across a time course of estradiol (E2) stimulation in human estrogen receptor α (ERα)-positive breast cancer cells. We identified subsets of temporally highly dynamic compartments predominantly associated with active open chromatin and found that these highly dynamic compartments showed higher alteration in tamoxifen-resistant breast cancer cells. Remarkably, these compartments are characterized by active chromatin states, and enhanced ERα binding but decreased transcription factor CCCTC-binding factor (CTCF) binding. We finally identified a set of ERα-bound promoter-enhancer looping genes enclosed within altered domains that are enriched with cancer invasion, aggressiveness or metabolism signaling pathways. This large-scale analysis expands our understanding of high-order temporal chromatin reorganization underlying hormone-dependent breast cancer.

Li W, Cao J, Liu J, et al.
Downregulation of CDKL1 suppresses neuroblastoma cell proliferation, migration and invasion.
Cell Mol Biol Lett. 2019; 24:19 [PubMed] Article available free on PMC after 13/11/2019 Related Publications
Background: Cyclin-dependent kinase-like 1 (CDKL1) is a member of the cell division control protein 2-related serine-threonine protein kinase family. It is known to occur in various malignant tumors, but its role in neuroblastoma (NB) remains unclear.
Methods: We constructed a CDKL1-silenced NB cell strain (SH-SY5Y) and used real-time PCR and western blotting to confirm the silencing. Functional analyses were performed using the MTT, colony-formation, FACS, wound-healing and transwell invasion assays.
Results: The expression of CDKL1 was significantly upregulated in NB tissue as compared to the adjacent normal tissue. CDKL1 knockdown significantly suppressed cell viability and colony formation ability. It also induced cell cycle G0/G1 phase arrest and apoptosis, and suppressed the migration and invasion ability of SH-SY5Y cells. CDKL1 knockdown decreased the CDK4, cyclin D1 and vimentin expression levels, and increased the caspase-3, PARP and E-cadherin expression levels in SH-SY5Y cells.
Conclusions: Our findings suggest that CDKL1 plays an important role in NB cell proliferation, migration and invasion. It might serve as a potential target for NB therapy.

Nunes-Xavier CE, Zaldumbide L, Aurtenetxe O, et al.
Dual-Specificity Phosphatases in Neuroblastoma Cell Growth and Differentiation.
Int J Mol Sci. 2019; 20(5) [PubMed] Article available free on PMC after 13/11/2019 Related Publications
Dual-specificity phosphatases (DUSPs) are important regulators of neuronal cell growth and differentiation by targeting proteins essential to neuronal survival in signaling pathways, among which the MAP kinases (MAPKs) stand out. DUSPs include the MAPK phosphatases (MKPs), a family of enzymes that directly dephosphorylate MAPKs, as well as the small-size atypical DUSPs, a group of low molecular-weight enzymes which display more heterogeneous substrate specificity. Neuroblastoma (NB) is a malignancy intimately associated with the course of neuronal and neuroendocrine cell differentiation, and constitutes the source of more common extracranial solid pediatric tumors. Here, we review the current knowledge on the involvement of MKPs and small-size atypical DUSPs in NB cell growth and differentiation, and discuss the potential of DUSPs as predictive biomarkers and therapeutic targets in human NB.

Oh JM, Lee J, Im WT, Chun S
Ginsenoside Rk1 Induces Apoptosis in Neuroblastoma Cells Through Loss of Mitochondrial Membrane Potential and Activation of Caspases.
Int J Mol Sci. 2019; 20(5) [PubMed] Article available free on PMC after 13/11/2019 Related Publications
Neuroblastoma (NB) is the most common childhood cancer, with a very poor prognosis. More than 60% of children with NB die within five years; therefore, a more effective therapy for NB is required. Although ginsenoside has been shown to significantly inhibit the growth of various cancers, the effect of ginsenoside Rk1 on neuroblastoma has not been known yet. Hence, we examined the anticancer effects of highly pure Rk1 on neuroblastoma cell lines. The apoptotic effects of Rk1 on neuroblastoma cells were examined using cell viability assay, flow cytometry and cell staining assay, and the change in gene expression levels were analysed using RT-PCR, western blots, and immunohistochemistry. The metastatic effect of Rk1 was monitored by wound healing assay, invasion and migration with Matrigels. Rk1 inhibited neuroblastoma cell viability dose-dependently. Rk1-induced apoptosis was investigated through nuclear condensation and mitochondrial membrane potential loss, and it showed that Rk1 can induce cell cycle arrest at the G0/G1 phase but also inhibit the metastatic ability of neuroblastoma cells. Moreover, Rk1 (30 mg/kg) injections markedly inhibited xenograft tumor growth. These findings demonstrate that Rk1 might be valuable in the development of anti-cancer agents for neuroblastoma treatment.

Li S, Zhang W, Jiang K, et al.
Nanobody against the E7 oncoprotein of human papillomavirus 16.
Mol Immunol. 2019; 109:12-19 [PubMed] Related Publications
The persistent infection of high-risk human papillomavirus (HPV) is one of the most common causes of cervical cancer. It is well documented that expression of two oncogenes (E6/E7) plays a key role in tumor progression. HPV16E7 -targeting via nanobody (Nb) therefore could be beneficial for HPV16-associated cancer diagnosis and therapy. In this work, phage-display approach was employed to select the high affinity HPV16E7-specific Nb. Firstly; a high-quality immune library was constructed. After three round of biopanning, high-affinity HPV16 E7-specific nanobodies were retrieved. By phage ELISA and sequencing, four different sequences of anti- HPV16E7 nanobodies were selected. Then recombinant nanobody Nb2 was cloned and expressed in E. coli, and the specificity and thermal stability of purified Nb2 was evaluated. To examine the potential of Nb2 as an inhibitor of E7 function, Nb2 was expressed within HPV16 positive cells. Proliferation assay showed that the intracellular expressed Nb2 as an intrabody can decrease the growth of HPV16-positive cells. The results indicate that Nb2 as an intracellular antibody directed towards HPV oncoprotein E7 has great promise in applications for the therapy of HPV16-associated disease.

Rajakulendran N, Rowland KJ, Selvadurai HJ, et al.
Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells.
Genes Dev. 2019; 33(9-10):498-510 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/βcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/βcatenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/βcatenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnt

Saqafi B, Rahbarizadeh F
Polyethyleneimine-polyethylene glycol copolymer targeted by anti-HER2 nanobody for specific delivery of transcriptionally targeted tBid containing construct.
Artif Cells Nanomed Biotechnol. 2019; 47(1):501-511 [PubMed] Related Publications
The present research seeks to investigate the process of mixing targeted gene delivery and transcriptional targeting. We have conjugated Polyethylenimine polymers (PEI) and molecules of poly (ethylene glycol). The next step was covalent attachment of anti-HER2 variables domains of camelid heavy chains antibodies (VHHs) or nanobodies (Nbs) to the distal terminals of NHS-PEG3500 in PEI-PEG nanoparticles. The whole procedure yielded PEI-PEG-Nb immunoconjugates. Having determined the properties of polyplexes, steps were taken to investigate the most efficient ratio of PEI polymers to pDNA molecules (N/P) so that the greatest rate of transfection may be obtained. This immune targeted nano biopolymer could condense the gene constructs that coded a transcriptionally targeted truncated -Bid (tBid) killer gene which was controlled by the breast cancer-specific MUC1 promoter. The favourable physicochemical properties matching both the size and zeta potential were observed in engineered polyplexes. Elevated transfection efficiency in HER2 positive cell lines using Nb-modified polyplexes were shown by the results of flow cytometry as compared against non-modified particles. 1.6 and 4.8 fold higher transfection efficiencies were observed in in vitro gene expression researches which used PEI-PEG-Nb/pGL4.50 compared to the situation when native PEI polymers were utilized in both BT-474 and SK-BR-3, respectively. A 2.22 and 3.62 fold rise in the level of tBid gene expression in BT-474 and SK-BR-3 cell lines relative to unmodified PEI treated cells was the result of transfection with PEI-PEG-Nb/pMUC1-tBid, respectively. In those HER2-positive cells which were transfected by targeted polyplexes, higher levels of cell death were observed. This fact points not only to the effective targeted delivery, but it is also indicative of transcriptional targeting efficiency of tBid killer gene when its expression is controlled by MUC1 promoter.

Jia D, Lu M, Jung KH, et al.
Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways.
Proc Natl Acad Sci U S A. 2019; 116(9):3909-3918 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Metabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis and metastasis. However, it is still largely unknown how cancer cells orchestrate gene regulation to balance their glycolysis and OXPHOS activities. Previously, by modeling the gene regulation of cancer metabolism we have reported that cancer cells can acquire a stable hybrid metabolic state in which both glycolysis and OXPHOS can be used. Here, to comprehensively characterize cancer metabolic activity, we establish a theoretical framework by coupling gene regulation with metabolic pathways. Our modeling results demonstrate a direct association between the activities of AMPK and HIF-1, master regulators of OXPHOS and glycolysis, respectively, with the activities of three major metabolic pathways: glucose oxidation, glycolysis, and fatty acid oxidation. Our model further characterizes the hybrid metabolic state and a metabolically inactive state where cells have low activity of both glycolysis and OXPHOS. We verify the model prediction using metabolomics and transcriptomics data from paired tumor and adjacent benign tissue samples from a cohort of breast cancer patients and RNA-sequencing data from The Cancer Genome Atlas. We further validate the model prediction by in vitro studies of aggressive triple-negative breast cancer (TNBC) cells. The experimental results confirm that TNBC cells can maintain a hybrid metabolic phenotype and targeting both glycolysis and OXPHOS is necessary to eliminate their metabolic plasticity. In summary, our work serves as a platform to symmetrically study how tuning gene activity modulates metabolic pathway activity, and vice versa.

Pal R, Xiong Y, Sardiello M
Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent signaling pathways.
Proc Natl Acad Sci U S A. 2019; 116(8):2977-2986 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that causes tumor formation in multiple organs. TSC is caused by inactivating mutations in the genes encoding TSC1/2, negative regulators of the mammalian target of rapamycin complex 1 (mTORC1). Diminished TSC function is associated with excess glycogen storage, but the causative mechanism is unknown. By studying human and mouse cells with defective or absent TSC2, we show that complete loss of TSC2 causes an increase in glycogen synthesis through mTORC1 hyperactivation and subsequent inactivation of glycogen synthase kinase 3β (GSK3β), a negative regulator of glycogen synthesis. Specific TSC2 pathogenic mutations, however, result in elevated glycogen levels with no changes in mTORC1 or GSK3β activities. We identify mTORC1-independent lysosomal depletion and impairment of autophagy as the driving causes underlying abnormal glycogen storage in TSC irrespective of the underlying mutation. The defective autophagic degradation of glycogen is associated with abnormal ubiquitination and degradation of essential proteins of the autophagy-lysosome pathway, such as LC3 and lysosomal associated membrane protein 1 and 2 (LAMP1/2) and is restored by the combined use of mTORC1 and Akt pharmacological inhibitors. In complementation to current models that place mTORC1 as the central therapeutic target for TSC pathogenesis, our findings identify mTORC1-independent pathways that are dysregulated in TSC and that should therefore be taken into account in the development of a therapeutic treatment.

Cheng X, Xu Q, Zhang Y, et al.
miR-34a inhibits progression of neuroblastoma by targeting autophagy-related gene 5.
Eur J Pharmacol. 2019; 850:53-63 [PubMed] Related Publications
Neuroblastoma (NB) is a common pediatric malignancy with high mortality in childhood. Although many attentions have been gained, novel biomarkers for NB diagnosis and prognosis are still needed. microRNAs (miRNAs) played important roles in NB progression and miR-34a is a tumor suppressor in NB. However, the mechanism that underlies miR-34a regulating proliferation, migration, invasion and autophagy in NB remains poorly understood. In this study, cell proliferation was investigated by MTT and colony assay. Cell apoptosis was measured by caspase 3 activity assay. Cell migration and invasion were detected by trans-well analysis. Autophagy was measured via GFP-LC3 puncta fluorescence assay and western blots (WB). The expression of miR-34a was examined by quantitative real-time PCR (qRT-PCR). The regulatory effect of miR-34a on autophagy-related gene 5 (ATG5) was detected by qRT-PCR and WB. The interaction between miR-34a and ATG5 was probed by luciferase activity and RNA immunoprecipitation (RIP) assay. Results showed that miR-34a expression was inhibited in NB tissues and cells with low survival rate. Addition of miR-34a suppressed cell proliferation, migration, invasion and autophagy but promoted apoptosis in NB cells, whereas miR-34a deficiency played opposite roles in NB progression. Intriguingly, ATG5 was directly targeted by miR-34a. Moreover, ATG5 restoration attenuated miR-34a-mediated inhibitory effect on proliferation, apoptosis, migration, invasion and autophagy. These results indicated miR-34a suppressed proliferation, apoptosis, migration, invasion and autophagy in NB cells by targeting ATG5, providing a novel therapeutic avenue for NB treatment.

Somasundaram DB, Aravindan S, Yu Z, et al.
Droplet digital PCR as an alternative to FISH for MYCN amplification detection in human neuroblastoma FFPE samples.
BMC Cancer. 2019; 19(1):106 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: MYCN amplification directly correlates with the clinical course of neuroblastoma and poor patient survival, and serves as the most critical negative prognostic marker. Although fluorescence in situ hybridization (FISH) remains the gold standard for clinical diagnosis of MYCN status in neuroblastoma, its limitations warrant the identification of rapid, reliable, less technically challenging, and inexpensive alternate approaches.
METHODS: In the present study, we examined the concordance of droplet digital PCR (ddPCR, in combination with immunohistochemistry, IHC) with FISH for MYCN detection in a panel of formalin-fixed paraffin-embedded (FFPE) human neuroblastoma samples.
RESULTS: In 112 neuroblastoma cases, ddPCR analysis demonstrated a 96-100% concordance with FISH. Consistently, IHC grading revealed 92-100% concordance with FISH. Comparing ddPCR with IHC, we observed a concordance of 95-98%.
CONCLUSIONS: The results demonstrate that MYCN amplification status in NB cases can be assessed with ddPCR, and suggest that ddPCR could be a technically less challenging method of detecting MYCN status in FFPE specimens. More importantly, these findings illustrate the concordance between FISH and ddPCR in the detection of MYCN status. Together, the results suggest that rapid, less technically demanding, and inexpensive ddPCR in conjunction with IHC could serve as an alternate approach to detect MYCN status in NB cases, with near-identical sensitivity to that of FISH.

Kriseman M, Monsivais D, Agno J, et al.
Uterine double-conditional inactivation of
Proc Natl Acad Sci U S A. 2019; 116(9):3873-3882 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
SMAD2 and SMAD3 are downstream proteins in the transforming growth factor-β (TGF β) signaling pathway that translocate signals from the cell membrane to the nucleus, bind DNA, and control the expression of target genes. While SMAD2/3 have important roles in the ovary, we do not fully understand the roles of SMAD2/3 in the uterus and their implications in the reproductive system. To avoid deleterious effects of global deletion, and given previous data showing redundant function of

Marin Navarro A, Day K, Kogner P, et al.
Generation of induced pluripotent stem cell lines from two Neuroblastoma patients carrying a germline ALK R1275Q mutation.
Stem Cell Res. 2019; 34:101356 [PubMed] Related Publications
Neuroblastoma (NB) is an embryonic tumor of the peripheral nervous system and one of the most common solid cancers in infants. Mutations in the Anaplastic lymphoma tyrosine kinase (ALK) gene are common in NB. To study the contribution of ALK mutations in NB initiation and progression, we reprogrammed fibroblasts from two related NB patients carrying germline mutations in ALK (R1275Q) using non-integrating Sendai virus. The iPS cells are grown in a feeder- and xeno-free conditions, have normal karyotype, retain the ALK R1275Q mutation, have been characterized by expression of pluripotency markers and differentiation to all three germ layers.

Popov A, Druy A, Shorikov E, et al.
Prognostic value of initial bone marrow disease detection by multiparameter flow cytometry in children with neuroblastoma.
J Cancer Res Clin Oncol. 2019; 145(2):535-542 [PubMed] Related Publications
PURPOSE: Multicolor flow cytometry (MFC) is widely available, fast and has an easy-to perform approach for finding neuroblastoma (NB) cells among normal bone marrow (BM) hematopoietic cells. Aim of the study was to investigate prognostic significance of initial MFC tumor cells' detection in BM of children with NB.
METHODS: 51 patients (24 boys and 27 girls) aged from 6 days to 15 years (median age 1 year 3 months) with NB were included in the study. BM samples at the time of diagnosis were obtained from 2 to 5 aspiration sites per patient. CD45(-)CD56(+)CD81(+)GD2(+)-cells were evaluated by MFC.
RESULTS: NB cells were detected in BM by FC more frequently compared to conventional cytomorphology (49.0% and 29.4% patients, respectively, р = 0.043). Patients with NB cells detected in BM by MFC had significantly worse event-free survival and cumulative incidence of relapse/progression [0.24(0.08) and 0.60(0.10), respectively] compared to children with negative result of immunophenotyping [0.85(0.07) and 0.12(0.06), respectively, p < 0.001 in both cases]. BM involvement detection by MFC maintained its prognostic significance in various patients groups. In multivariate analysis, immunophenotyping proved to be an independent prognostic factor when analyzed jointly with other NB risk factors. In 42 patients BM involvement was also studied by RQ-PCR for PHOX2B and TH genes expression. Within groups of patients divided by RQ-PCR positivity, MFC-positivity retained prognostic significance.
CONCLUSIONS: Thus flow cytometric BM involvement detection has very strong prognostic impact even stronger than RQ-PCR. It could be used in combination with other parameters for the treatment strategy choice in patients with NB.

Peng Y, Xing SN, Tang HY, et al.
Influence of glucose transporter 1 activity inhibition on neuroblastoma in vitro.
Gene. 2019; 689:11-17 [PubMed] Related Publications
Most cancer cells predominantly produce their energy through a high rate of glycolysis in the presence of abundant oxygen. Glycolysis has become a target of anticancer strategies. Previous researches showed that glucose transporter 1 (GLUT1) inhibitor is effective as anticancer agents. This study assessed the effects of the selective GLUT1 inhibitor WZB117 on regulation of neuroblastoma (NB) cell line SH-SY5Y viability, cell cycle and glycolysis in vitro. SH-SY5Y cells were grown and treated with WZB117 for up to 72 h and then subjected to cell viability, qRT-PCR, Western blot and flow cytometry analysis. Level of ATP and LDH was also analyzed. The result showed that WZB117 treatment reduced tumor cells viability, downregulated level of GLUT1 protein. Moreover, WZB117 treatment arrested tumor cells at the G0-G1 phase of the cell cycle, induced tumor cells to undergo necrosis instead of apoptosis. In addition, WZB117 treatment downregulated the levels of intracellular ATP, LDH and glycolytic enzymes. Thus, WZB117-induced GLUT1 inhibition suppressed tumor cell growth, induced cell cycle arrest and reduced glycolysis metabolites in NB cells in vitro. This study suggested that GLUT1 can be used as a potential therapeutic target for NB.

Pelizzo G, Veschi V, Mantelli M, et al.
Microenvironment in neuroblastoma: isolation and characterization of tumor-derived mesenchymal stromal cells.
BMC Cancer. 2018; 18(1):1176 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: It has been proposed that mesenchymal stromal cells (MSCs) promote tumor progression by interacting with tumor cells and other stroma cells in the complex network of the tumor microenvironment. We characterized MSCs isolated and expanded from tumor tissues of pediatric patients diagnosed with neuroblastomas (NB-MSCs) to define interactions with the tumor microenvironment.
METHODS: Specimens were obtained from 7 pediatric patients diagnosed with neuroblastoma (NB). Morphology, immunophenotype, differentiation capacity, proliferative growth, expression of stemness and neural differentiation markers were evaluated. Moreover, the ability of cells to modulate the immune response, i.e. inhibition of phytohemagglutinin (PHA) activated peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cytotoxic function, was examined. Gene expression profiles, known to be related to tumor cell stemness, Wnt pathway activation, epithelial-mesenchymal transition (EMT) and tumor metastasis were also evaluated. Healthy donor bone marrow-derived MSCs (BM-MSC) were employed as controls.
RESULTS: NB-MSCs presented the typical MSC morphology and phenotype. They showed a proliferative capacity superimposable to BM-MSCs. Stemness marker expression (Sox2, Nanog, Oct3/4) was comparable to BM-MSCs. NB-MSC in vitro osteogenic and chondrogenic differentiation was similar to BM-MSCs, but NB-MSCs lacked adipogenic differentiation capacity. NB-MSCs reached senescence phases at a median passage of P7 (range, P5-P13). NB-MSCs exhibited greater immunosuppressive capacity on activated T lymphocytes at a 1:2 (MSC: PBMC) ratio compared with BM-MSCs (p = 0.018). NK cytotoxic activity was not influenced by co-culture, either with BM-MSCs or NB-MSCs. Flow-cytometry cell cycle analysis showed that NB-MSCs had an increased number of cells in the G0-G1 phase compared to BM-MSCs. Transcriptomic profiling results indicated that NB-MSCs were enriched with EMT genes compared to BM-MSCs.
CONCLUSIONS: We characterized the biological features, the immunomodulatory capacity and the gene expression profile of NB-MSCs. The NB-MSC gene expression profile and their functional properties suggest a potential role in promoting tumor escape, invasiveness and metastatic traits of NB cancer cells. A better understanding of the complex mechanisms underlying the interactions between NB cells and NB-derived MSCs should shed new light on potential novel therapeutic approaches.

Bauchet L, Ostrom QT
Epidemiology and Molecular Epidemiology.
Neurosurg Clin N Am. 2019; 30(1):1-16 [PubMed] Related Publications
Incidence, prevalence, and survival for diffuse low-grade gliomas and diffuse anaplastic gliomas (including grade II and grade III astrocytomas and oligodendrogliomas) varies by histologic type, age at diagnosis, sex, and race/ethnicity. Significant progress has been made in identifying potential risk factors for glioma, although more research is warranted. The strongest risk factors that have been identified thus far include allergies/atopic disease, ionizing radiation, and heritable genetic factors. Further analysis of large, multicenter epidemiologic studies, and well-annotated "omic" datasets, can potentially lead to further understanding of the relationship between gene and environment in the process of brain tumor development.

Fang E, Wang J, Hong M, et al.
Valproic acid suppresses Warburg effect and tumor progression in neuroblastoma.
Biochem Biophys Res Commun. 2019; 508(1):9-16 [PubMed] Related Publications
Altered glucose metabolism is a hallmark for cancer, which is characterized by a unique metabolic phenotype known as Warburg effect or aerobic glycolysis. Emerging studies show that valproic acid (VPA), an established histone deacetylase inhibitor, possesses tumor suppressive properties. However, the effects of VPA on the regulation of Warburg effect in neuroblastoma (NB), the most common extracranial malignancy in childhood, still remain elusive. In this study, we show that VPA inhibits the aerobic glycolysis in NB cells by decreasing glucose uptake and reducing lactate and ATP production. Mechanistically, VPA suppresses aerobic glycolysis via reducing the levels of E2F transcription factor 1 (E2F1), resulting in repressed expression of glycolytic genes glucose-6-phosphate isomerase (GPI) and phosphoglycerate pinase 1 (PGK1). Rescue experiments show that VPA inhibits the aerobic glycolysis and NB progression through down-regulation of E2F1. These results demonstrate that VPA suppresses the Warburg effect and tumor progression, indicating a novel therapeutic strategy for NB.

Shakhova I, Li Y, Yu F, et al.
PPP3CB contributes to poor prognosis through activating nuclear factor of activated T-cells signaling in neuroblastoma.
Mol Carcinog. 2019; 58(3):426-435 [PubMed] Related Publications
We previously identified a gain-of-function mutation in PPP3CB in a neuroblastoma (NB) with MYCN amplification. Here we investigated the functional and clinical role of PPP3CB in NB. High PPP3CB expression was an independent indicator predicting poor prognosis of NB. Overexpression of wildtype or mutated PPP3CB (PPP3CBmut) promoted cell growth, but PPP3CB knockdown decreased cell growth in NB cells. Forced expressions of PPP3CB and PPP3CBmut activated NFAT2 and NFAT4 transcription factors and inhibited GSK3β activity, resulting in the increase in the expressions of c-Myc, MYCN, and β-catenin, which were downregulated in response to PPP3CB knockdown. Treatment with calcineurin inhibitor cyclosporin A (CsA) or FK506 suppressed cell proliferation and induced apoptotic cell death in both MYCN-amplified and MYCN-non-amplified NB cell lines. Expression of PPP3CB protein was decreased in response to two calcineurin inhibitors. c-Myc, MYCN, and β-catenin were downregulated at the mRNA and protein levels in CsA or FK506-treated NB cells. Our data indicate that elevated expression of PPP3CB and the expression of its constitutively active mutant contribute to the aggressive behavior of NB tumors and therefore suggest that inhibition of calcineurin activity might have therapeutic potential for high-risk NB.

Marx M, Zumpe M, Troschke-Meurer S, et al.
Co-expression of IL-15 enhances anti-neuroblastoma effectivity of a tyrosine hydroxylase-directed DNA vaccination in mice.
PLoS One. 2018; 13(11):e0207320 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Long-term survival of high-risk neuroblastoma (NB) patients still remains under 50%. Here, we report the generation, in vitro characterization and anti-tumor effectivity of a new bicistronic xenogenic DNA vaccine encoding tyrosine hydroxylase (TH) that is highly expressed in NB tumors, and the immune stimulating cytokine interleukin 15 (IL-15) that induces cytotoxic but not regulatory T cells. The DNA sequences of TH linked to ubiquitin and of IL-15 were integrated into the bicistronic expression vector pIRES. Successful production and bioactivity of the vaccine-derived IL-15- and TH protein were shown by ELISA, bioactivity assay and western blot analysis. Further, DNA vaccine-driven gene transfer to the antigen presenting cells of Peyer's patches using attenuated Salmonella typhimurium that served as oral delivery system was shown by immunofluorescence analysis. The anti-tumor effect of the generated vaccine was evaluated in a syngeneic mouse model (A/J mice, n = 12) after immunization with S. typhimurium (3× prior and 3× after tumor implantation). Importantly, TH-/IL-15-based DNA vaccination resulted in an enhanced tumor remission in 45.5% of mice compared to controls (TH (16.7%), IL-15 (0%)) and reduced spontaneous metastasis (30.0%) compared to controls (TH (63.6%), IL-15 (70.0%)). Interestingly, similar levels of tumor infiltrating CD8+ T cells were observed among all experimental groups. Finally, co-expression of IL-15 did not result in elevated regulatory T cell levels in tumor environment measured by flow cytometry. In conclusion, co-expression of the stimulatory cytokine IL-15 enhanced the NB-specific anti-tumor effectivity of a TH-directed vaccination in mice and may provide a novel immunological approach for NB patients.

Zhao Z, Hao D, Wang L, et al.
CtBP promotes metastasis of breast cancer through repressing cholesterol and activating TGF-β signaling.
Oncogene. 2019; 38(12):2076-2091 [PubMed] Related Publications
Metastasis is the process through which the primary cancer cells spread beyond the primary tumor and disseminate to other organs. Most cancer patients die of metastatic disease. EMT is proposed to be the initial event associated with cancer metastasis and how it occurred is still a mystery. CtBP is known as a co-repressor abundantly expressed in many types of cancer and regulates genes involved in cancer initiation, progression, and metastasis. We found that CtBP regulates intracellular cholesterol homeostasis in breast cancer cells by forming a complex with ZEB1 and transcriptionally repressing SREBF2 expression. Importantly, CtBP repression of intracellular cholesterol abundance leads to increased EMT and cell migration. The reason is that cholesterol negatively regulates the stability of TGF-β receptors on the cell membrane. Interestingly, TGF-β is also capable of reducing intracellular cholesterol relying on the increased recruitment of ZEB1 and CtBP complex to SREBF2 promoter. Thus, we propose a feedback loop formed by CtBP, cholesterol, and TGF-β signaling pathway, through which TGF-β triggers the cascade that mobilizes the cancer cells for metastasis. Consistently, the intravenous injection of breast cancer cells with ectopically CtBP expression show increased lung metastasis depending on the reduction of intracellular cholesterol. Finally, we analyzed the public breast cancer datasets and found that CtBP expression negatively correlates with SREBF2 and HMGCR expressions. High expression of CtBP and low expression of SREBF2 and HMGCR significantly correlates with high EMT of the primary tumors.

Wang H, Tian L, Liu J, et al.
The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability.
Cancer Cell. 2018; 34(5):823-839.e7 [PubMed] Article available free on PMC after 12/11/2019 Related Publications
The fate of disseminated tumor cells is largely determined by microenvironment (ME) niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using pre-clinical models and analyses of clinical data. We discovered that the osteogenic niche serves as a calcium (Ca) reservoir for cancer cells through gap junctions. Cancer cells cannot efficiently absorb Ca from ME, but depend on osteogenic cells to increase intracellular Ca concentration. The Ca signaling, together with previously identified mammalian target of rapamycin signaling, promotes bone metastasis progression. Interestingly, effective inhibition of these pathways can be achieved by danusertib, or a combination of everolimus and arsenic trioxide, which provide possibilities of eliminating bone micrometastases using clinically established drugs.

Cheng C, Xiaohua W, Ning J, et al.
MiR-122 exerts anti-proliferative and apoptotic effects on nasopharyngeal carcinoma cells via the PI3K/AKT signaling pathway.
Cell Mol Biol (Noisy-le-grand). 2018; 64(13):21-25 [PubMed] Related Publications
To investigate the effects of microRNA-122 (miR-122) on the proliferation and apoptosis of nasopharyngeal carcinoma (NPC) HONE-1 cells, and its correlation with the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Human NPC cell line (HONE-1) was transfected with miR-122 inhibitor (anti-miR-122 group), negative controls (vector control group) via lipofectamines, and HONE-1 cell lines undergoing no transfection were selected (non-transfection group). The expression of miR-122, cell proliferation, apoptosis, and expressions of PI3K/AKT pathway and downstream target proteins in the three groups were determined using fluorescence quantitative polymerase chain reaction (qPCR), cell counting kit-8 (CCK8), immunofluorescence (IF) and Western blotting, respectively. The expression of miR-122 in the anti-miR-122 group was significantly lower than corresponding expressions in the non-transfection and vector control groups after 48h of transfection (p <0.05). The proliferation of cells in the anti-miR-122 group was significantly reduced with time after transfection (p <0.05). After 48h of transfection, the extent of apoptosis in the anti-miR-122 group (47.11 ± 1.95%) was significantly higher than that in normal control (7.37 ± 0.82%) and vector control group (8.54 ± 0.96%; p <0.05). There were no significant differences in the expressions of PI3K, AKT, mTOR protein, and the downstream signal proteins (p70S6K and 4E-BP1) in the three groups (p >0.05). However, the expressions of phosphorylated forms of these proteins were significantly lower in the anti-miR-122 group than in the non-transfection and vector control groups (p <0.05). IF results revealed that there were no significant differences in the fluorescence intensity value of PI3K and Akt among the three groups of patients (p>0.05). Inhibition of the expression of miR-122 in NPC suppresses the proliferation, and promotes their apoptosis through the PI3K/AKT signal transduction pathway.

Foroutan M, Bhuva DD, Lyu R, et al.
Single sample scoring of molecular phenotypes.
BMC Bioinformatics. 2018; 19(1):404 [PubMed] Article available free on PMC after 12/11/2019 Related Publications
BACKGROUND: Gene set scoring provides a useful approach for quantifying concordance between sample transcriptomes and selected molecular signatures. Most methods use information from all samples to score an individual sample, leading to unstable scores in small data sets and introducing biases from sample composition (e.g. varying numbers of samples for different cancer subtypes). To address these issues, we have developed a truly single sample scoring method, and associated R/Bioconductor package singscore ( https://bioconductor.org/packages/singscore ).
RESULTS: We use multiple cancer data sets to compare singscore against widely-used methods, including GSVA, z-score, PLAGE, and ssGSEA. Our approach does not depend upon background samples and scores are thus stable regardless of the composition and number of samples being scored. In contrast, scores obtained by GSVA, z-score, PLAGE and ssGSEA can be unstable when less data are available (N
CONCLUSIONS: The singscore method described here functions independent of sample composition in gene expression data and thus it provides stable scores, which are particularly useful for small data sets or data integration. Singscore performs well across all performance criteria, and includes a suite of powerful visualization functions to assist in the interpretation of results. This method performs as well as or better than other scoring approaches in terms of its power to distinguish samples with distinct biology and its ability to call true differential gene sets between two conditions. These scores can be used for dimensional reduction of transcriptomic data and the phenotypic landscapes obtained by scoring samples against multiple molecular signatures may provide insights for sample stratification.

Lin X, Han L, Weng J, et al.
Rapamycin inhibits proliferation and induces autophagy in human neuroblastoma cells.
Biosci Rep. 2018; 38(6) [PubMed] Article available free on PMC after 12/11/2019 Related Publications

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