Functional interplay between <scp>MYCN</scp>,<scp> NCYM</scp>, and <scp>OCT</scp>4 promotes aggressiveness of human neuroblastomas

Kaneko, Yoshiki; Suenaga, Yusuke; Islam, S.M. Rafiqul; Matsumoto, Daisuke; Nakamura, Yohko; Ohira, Miki; Yokoi, Sana; Nakagawara, Akira

doi:10.1111/cas.12677

Cited by 46 publications

(60 citation statements)

References 27 publications

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“…(32) Therefore, overexpression of reprogramming factors may contribute to chemoresistance in MYCN-non amplified SH-IN cells, possibly by induction of these stem-cell related genes. (29)(30)(31)(32)35,36) Our present findings indicate that partially reprogrammed NB cells could be a valuable in vitro model for understanding how NB cells maintain plasticity and aggressiveness.…”

Section: Discussionmentioning

confidence: 59%

“…Previous reports suggest that the expression level of MYCN is not associated with poor prognosis in MYCN non‐amplified NBs, while the level of NCYM is associated with poor prognosis . Therefore, overexpression of reprogramming factors may contribute to chemoresistance in MYCN ‐non amplified SH‐IN cells, possibly by induction of these stem‐cell related genes …”

Section: Discussionmentioning

confidence: 97%

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Sendai virus‐mediated expression of reprogramming factors promotes plasticity of human neuroblastoma cells

et al. 2015

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Neuroblastoma (NB) is the most common extracranial solid tumor that originates from multipotent neural crest cells. NB cell populations that express embryonic stem cell-associated genes have been identified and shown to retain a multipotent phenotype. However, whether somatic reprogramming of NB cells can produce similar stem-cell like populations is unknown. Here, we sought to reprogram NB cell lines using an integration-free Sendai virus vector system. Of four NB cell lines examined, only SH-IN cells formed induced pluripotent stem cell-like colonies (SH-IN 4F colonies) at approximately 6 weeks following transduction. These SH-IN 4F colonies were alkaline phosphatase-positive. Array comparative genomic hybridization analysis indicated identical genomic aberrations in the SH-IN 4F cells as in the parental cells. SH-IN 4F cells had the ability to differentiate into the three embryonic germ layers in vitro, but rather formed NBs in vivo. Furthermore, SH-IN 4F cells exhibited resistance to cisplatin treatment and differentiated into endothelial-like cells expressing CD31 in the presence of vascular endothelial growth factor. These results suggest that SH-IN 4F cells are partially reprogrammed NB cells, and could be a suitable model for investigating the plasticity of aggressive tumors.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 97%

Sendai virus‐mediated expression of reprogramming factors promotes plasticity of human neuroblastoma cells

et al. 2015

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“…2). Furthermore, all steady states had MYCN ‘OFF’ and p27 ‘ON’, identifiers of less aggressive and more differentiated tumors, respectively (52,53). …”

Section: Discussionmentioning

confidence: 99%

Predicting neuroblastoma using developmental signals and a logic-based model

Kasemeier-Kulesa

Schnell

Woolley

et al. 2018

Biophysical Chemistry

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SUMMARY Genomic information from human patient samples of pediatric neuroblastoma cancers and known outcomes have led to specific gene lists put forward as high risk for disease progression. However, the reliance on gene expression correlations rather than mechanistic insight has shown limited potential and suggests a critical need for molecular network models that better predict neuroblastoma progression. In this study, we construct and simulate a molecular network of developmental genes and downstream signals in a 6-gene input logic model that predicts a favorable/unfavorable outcome based on the outcome of the four cell states including cell differentiation, proliferation, apoptosis, and angiogenesis. We simulate the mis-expression of the tyrosine receptor kinases, trkA and trkB, two prognostic indicators of neuroblastoma, and find differences in the number and probability distribution of steady state outcomes. We validate the mechanistic model assumptions using RNAseq of the SHSY5Y human neuroblastoma cell line to define the input states and confirm the predicted outcome with antibody staining. Lastly, we apply input gene signatures from 77 published human patient samples and show that our model makes more accurate disease outcome predictions for early stage disease than any current neuroblastoma gene list. These findings highlight the predictive strength of a logic-based model based on developmental genes and offer a better understanding of the molecular network interactions during neuroblastoma disease progression.

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“…However, Oct-4 is considered as a master pluripotency gene and is expressed in side-population cells of NB [ 58 ]. Knockdown of Oct-4 inhibited the formation of spheres and the CD133 expression in MYCN-amplified human NBs cells [ 59 ]. Additionally, high Oct-4 expression was correlated with poor prognosis especially in patients with MYCN-amplified NBs [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Valproic Acid Increases CD133 Positive Cells that Show Low Sensitivity to Cytostatics in Neuroblastoma

Khalil

Hraběta

Groh³

et al. 2016

PLoS ONE

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Valproic acid (VPA) is a well-known antiepileptic drug that exhibits antitumor activities through its action as a histone deacetylase inhibitor. CD133 is considered to be a cancer stem cell marker in several tumors including neuroblastoma. CD133 transcription is strictly regulated by epigenetic modifications. We evaluated the epigenetic effects of treatment with 1mM VPA and its influence on the expression of CD133 in four human neuroblastoma cell lines. Chemoresistance and cell cycle of CD133+ and CD133− populations were examined by flow cytometry. We performed bisulfite conversion followed by methylation-sensitive high resolution melting analysis to assess the methylation status of CD133 promoters P1 and P3. Our results revealed that VPA induced CD133 expression that was associated with increased acetylation of histones H3 and H4. On treatment with VPA and cytostatics, CD133+ cells were mainly detected in the S and G2/M phases of the cell cycle and they showed less activated caspase-3 compared to CD133− cells. UKF-NB-3 neuroblastoma cells which express CD133 displayed higher colony and neurosphere formation capacities when treated with VPA, unlike IMR-32 which lacks for CD133 protein. Induction of CD133 in UKF-NB-3 was associated with increased expression of phosphorylated Akt and pluripotency transcription factors Nanog, Oct-4 and Sox2. VPA did not induce CD133 expression in cell lines with methylated P1 and P3 promoters, where the CD133 protein was not detected. Applying the demethylating agent 5-aza-2’-deoxycytidine to the cell lines with methylated promoters resulted in CD133 re-expression that was associated with a drop in P1 and P3 methylation level. In conclusion, CD133 expression in neuroblastoma can be regulated by histone acetylation and/or methylation of its CpG promoters. VPA can induce CD133+ cells which display high proliferation potential and low sensitivity to cytostatics in neuroblastoma. These results give new insight into the possible limitations to use VPA in cancer therapy.

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Functional interplay between MYCN, NCYM, and OCT4 promotes aggressiveness of human neuroblastomas

Cited by 46 publications

References 27 publications

Sendai virus‐mediated expression of reprogramming factors promotes plasticity of human neuroblastoma cells

Sendai virus‐mediated expression of reprogramming factors promotes plasticity of human neuroblastoma cells

Predicting neuroblastoma using developmental signals and a logic-based model

Valproic Acid Increases CD133 Positive Cells that Show Low Sensitivity to Cytostatics in Neuroblastoma

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