Article

N-Myc regulates expression of pluripotency genes in neuroblastoma including lif, klf2, klf4, and lin28b.

Department of Cell Biology and Human Anatomy, and Stem Cell Program, University of California Davis School of Medicine, Shriners Hospital For Children Northern California, Sacramento, California, USA.
PLoS ONE (Impact Factor: 3.53). 02/2009; 4(6):e5799. DOI: 10.1371/journal.pone.0005799
Source: PubMed

ABSTRACT myc genes are best known for causing tumors when overexpressed, but recent studies suggest endogenous myc regulates pluripotency and self-renewal of stem cells. For example, N-myc is associated with a number of tumors including neuroblastoma, but also plays a central role in the function of normal neural stem and precursor cells (NSC). Both c- and N-myc also enhance the production of induced pluripotent stem cells (iPSC) and are linked to neural tumor stem cells. The mechanisms by which myc regulates normal and neoplastic stem-related functions remain largely open questions. Here from a global, unbiased search for N-Myc bound genes using ChIP-chip assays in neuroblastoma, we found lif as a putative N-Myc bound gene with a number of strong N-Myc binding peaks in the promoter region enriched for E-boxes. Amongst putative N-Myc target genes in expression microarray studies in neuroblastoma we also found lif and three additional important embryonic stem cell (ESC)-related factors that are linked to production of iPSC: klf2, klf4, and lin28b. To examine the regulation of these genes by N-Myc, we measured their expression using neuroblastoma cells that contain a Tet-regulatable N-myc transgene (TET21N) as well as NSC with a nestin-cre driven N-myc knockout. N-myc levels closely correlated with the expression of all of these genes in neuroblastoma and all but lif in NSC. Direct ChIP assays also indicate that N-Myc directly binds the lif promoter. N-Myc regulates trimethylation of lysine 4 of histone H3 in the promoter of lif and possibly in the promoters of several other stem-related genes. Together these findings indicate that N-Myc regulates overlapping stem-related gene expression programs in neuroblastoma and NSC, supporting a novel model by which amplification of the N-myc gene may drive formation of neuroblastoma. They also suggest mechanisms by which Myc proteins more generally contribute to maintenance of pluripotency and self-renewal of ESC as well as to iPSC formation.

0 Bookmarks
 · 
97 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neuroblastoma is the most common extracranial solid tumor of children, accounting for an estimated 15% cancer-related deaths in this period. It has been hypothesized that drug resistance of cancer stem cells may be responsible for chemotherapy failure, sustained tumor growth, and recurrence in many solid tumors. In this study, we investigated the expression of Octamer-binding transcription factor 4 (Oct4) and Nanog, two stem cell markers, in 47 neuroblastic tumors by immunohistochemistry and correlated their expression by other prognostic factors especially with NMYC amplification using both fluorescent and chromogenic in situ hybridization methods. Twenty three cases (48.9%) showed Oct4 signals and eight cases (17%) showed Nanog expression. All Nanog positive tumors showed Oct4 expression. Seven cases (14.1%) had NMYC amplification. There was also no association between positive Oct4 and Nanog reactivity and tumor morphology, age, mitosis-karyorrhexis index, NMYC amplification, favorable or unfavorable histology, and risk groups (p > 0.05). Cancer stem cells hypothesis is a challenging issue and controversies exist about their significance. Although our study did not show strong association between prognostic factors and expression of stem cell markers, performing of further large-scale studies of various neuroblastic tumors with various stages is suggested.
    Apmis 12/2013; · 1.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In neuroblastoma, MYCN amplification is associated to a worse prognosis and is a criteria used in the clinic to provide intensive treatments to children even with localized disease. In correlation with MYCN amplification, upregulation of TWIST1, a transcription factor playing a crucial role in inhibition of apoptosis and differentiation was previously reported. Clinical data set analysis of MYCN, MYC and TWIST1 expression permit us to confirm that TWIST1 expression is upregulated in MYCN amplified neuroblastoma but also in a subset of neuroblastoma harboring high expression of MYCN or MYC without gene amplification. In silico analyses reveal the presence of several MYC regulatory motifs (E-Boxes and INR) within the TWIST1 promoter. Using gel shift assay and reporter activity assays, we demonstrate that both N-Myc and c-Myc proteins can bind and activate the TWIST1 promoter. Therefore, we propose TWIST1 as a direct MYC transcriptional target. Copyright © 2014. Published by Elsevier Ireland Ltd.
    Cancer Letters 12/2014; · 5.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: LIN28B is involved in "stemness" and tumourigenesis by negatively regulating the maturation of let-7 microRNA family members. In this study, we showed that LIN28B expression promotes migration and recurrence of colon cancer. Immunohistochemistry and reverse-transcription polymerase chain reactions were performed to detect LIN28B expression in colon cancer tissue microarrays, paraffin-embedded surgical resected tissues and cancer cells. Loss-of-function, migration and proliferation analyses were performed to delineate the potential roles of LIN28B in colon cancer. LIN28B was upregulated in colon cancer tissue compared to normal mucosa, and its overexpression correlated with reduced patient survival and increased tumour recurrence. LIN28B suppression inhibited the migration of SW480 colon cancer cells and facilitated the cytotoxicity induced by oxaliplatin in SW480 and HCT116 colon cancer cells. In conclusion, LIN28B overexpression contributes to colon tumourigenesis, and LIN28B may serve as a diagnostic tool and therapeutic target for colon cancer.
    PLoS ONE 10/2014; 9(10):e109169. · 3.53 Impact Factor

Preview (2 Sources)

Download
0 Downloads
Available from