Similar Datasets
Project description:LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis at least in part through inhibition of let-7 microRNA biogenesis. Here, we report that overexpression of either wild-type LIN28B, or a LIN28B mutant that is unable to bind and inhibit let-7, accelerates the onset and increases the penetrance of MYCN-induced neuroblastoma, potentiates the invasion and migration of transformed sympathetic neuroblasts and drives the distant metastases in vivo. Genome-wide ChIP-seq analysis and co-immunoprecipitation experiments show that LIN28B indirectly binds active gene promoters in neuroblastoma cells through an interaction with ZNF143 and activates the expression of downstream targets, including GSK3B and L1CAM, which are involved in neuronal cell adhesion and migration. These findings reveal an unexpected, let-7-independent function for LIN28B in transcriptional regulation during neuroblastoma pathogenesis.
2020-07-22 | GSE138741 | GEO
Project description:LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis at least in part through inhibition of let-7 microRNA biogenesis. Here, we report that overexpression of either wild-type LIN28B, or a LIN28B mutant that is unable to bind and inhibit let-7, accelerates the onset and increases the penetrance of MYCN-induced neuroblastoma, potentiates the invasion and migration of transformed sympathetic neuroblasts and drives the distant metastases in vivo. Genome-wide ChIP-seq analysis and co-immunoprecipitation experiments show that LIN28B indirectly binds active gene promoters in neuroblastoma cells through an interaction with ZNF143 and activates the expression of downstream targets, including GSK3B and L1CAM, which are involved in neuronal cell adhesion and migration. These findings reveal an unexpected, let-7-independent function for LIN28B in transcriptional regulation during neuroblastoma pathogenesis.
2020-07-22 | GSE138742 | GEO
Project description:LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis, at least, in part, through inhibition of let-7 microRNA biogenesis. Here, we report that overexpression of either wild-type (WT) LIN28B or a LIN28B mutant that is unable to inhibit let-7 processing increases the penetrance of MYCN-induced neuroblastoma, potentiates the invasion and migration of transformed sympathetic neuroblasts, and drives distant metastases in vivo. Genome-wide chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) and coimmunoprecipitation experiments show that LIN28B binds active gene promoters in neuroblastoma cells through protein-protein interaction with the sequence-specific zinc-finger transcription factor ZNF143 and activates the expression of downstream targets, including transcription factors forming the adrenergic core regulatory circuitry that controls the malignant cell state in neuroblastoma as well as GSK3B and L1CAM that are involved in neuronal cell adhesion and migration. These findings reveal an unexpected let-7-independent function of LIN28B in transcriptional regulation during neuroblastoma pathogenesis.
| S-EPMC7368283 | biostudies-literature
Project description:LIN28B Regulates Transcription and Potentiates MYCN-induced Neuroblastoma in a let-7-independent Manner
| PRJNA576941 | ENA
Project description:LIN28B Regulates Transcription and Potentiates MYCN-induced Neuroblastoma in a let-7-independent Manner [RNA-seq]
| PRJNA576945 | ENA
Project description:LIN28B Regulates Transcription and Potentiates MYCN-induced Neuroblastoma in a let-7-independent Manner [ChIP-seq]
| PRJNA576946 | ENA
Project description:LIN28B has been identified as an oncogene in various tumor entities, including neuroblastoma, a childhood cancer that originates from neural crest-derived cells, and is characterized by amplification of the MYCN oncogene. Recently, elevated LIN28B expression levels were shown to contribute to neuroblastoma tumorigenesis via let-7 dependent de-repression of MYCN. However, additional insight in the regulation of LIN28B in neuroblastoma is lacking. Therefore, we have performed a comprehensive analysis of the regulation of LIN28B in neuroblastoma, with a specific focus on the contribution of miRNAs. We show that MYCN regulates LIN28B expression in neuroblastoma tumors via two distinct parallel mechanisms. First, through an unbiased LIN28B-3'UTR reporter screen, we found that miR-26a-5p and miR-26b-5p regulate LIN28B expression. Next, we demonstrated that MYCN indirectly affects the expression of miR-26a-5p, and hence regulates LIN28B, therefore establishing an MYCN-miR-26a-5p-LIN28B regulatory axis. Second, we provide evidence that MYCN regulates LIN28B expression via interaction with the LIN28B promoter, establishing a direct MYCN-LIN28B regulatory axis. We believe that these findings mark LIN28B as an important effector of the MYCN oncogenic phenotype and underline the importance of MYCN-regulated miRNAs in establishing the MYCN-driven oncogenic process.
| S-EPMC4837470 | biostudies-literature
Project description:BackgroundMYCN amplification as a common genetic alteration that correlates with a poor prognosis for neuroblastoma (NB) patients. However, given the challenge of directly targeting MYCN, indirect strategies to modulate MYCN by interfering with its cofactors are attractive in NB treatment. Although cyclin B1 interacting protein 1 (CCNB1IP1) has been found to be upregulated in MYCN-driven mouse NB tissues, its regulation with MYCN and collaboration in driving the biological behaviour of NB remains unknown.MethodsTo evaluate the expression and clinical significance of CCNB1IP1 in NB patients, public datasets, clinical NB samples and cell lines were explored. MTT, EdU incorporation, colony and tumour sphere formation assays, and a mouse xenograft tumour model were utilized to examine the biological function of CCNB1IP1. The reciprocal manipulation of CCNB1IP1 and MYCN and the underlying mechanisms involved were investigated by gain- and loss-of-function approaches, dual-luciferase assay, chromatin immunoprecipitation (CHIP) and co-immunoprecipitation (Co-IP) experiments.ResultsCCNB1IP1 was upregulated in MYCN-amplified (MYCN-AM) NB cell lines and patients-derived tumour tissues, which was associated with poor prognosis. Phenotypic studies revealed that CCNB1IP1 facilitated the proliferation and tumourigenicity of NB cells in cooperation with MYCN in vitro and in vivo. Mechanistically, MYCN directly mediates the transcription of CCNB1IP1, which in turn attenuated the ubiquitination and degradation of MYCN protein, thus enhancing CCNB1IP1-MYCN cooperativity. Moreover, CCNB1IP1 competed with F box/WD-40 domain protein 7 (FBXW7) for MYCN binding and enabled MYCN-mediated tumourigenesis in a C-terminal domain-dependent manner.ConclusionsOur study revealed a previously uncharacterized mechanism of CCNB1IP1-mediated MYCN protein stability and will provide new prospects for precise treatment of MYCN-AM NB based on MYCN-CCNB1IP1 interaction.
| S-EPMC10352605 | biostudies-literature
Project description:Neuroblastoma is an aggressive pediatric malignancy of the neural crest with suboptimal cure rates and a striking predilection for widespread metastases, underscoring the need to identify novel therapeutic vulnerabilities. We recently identified the RNA binding protein LIN28B as a driver in high-risk neuroblastoma and demonstrated it promotes oncogenic cell proliferation by coordinating a RAN-Aurora kinase A network. Here, we demonstrate that LIN28B influences another key hallmark of cancer, metastatic dissemination. Using a murine xenograft model of neuroblastoma dissemination, we show that LIN28B promotes metastasis. We demonstrate that this is in part due to the effects of LIN28B on self-renewal and migration, providing an understanding of how LIN28B shapes the metastatic phenotype. Our studies reveal that the let-7 family, which LIN28B inhibits, decreases self-renewal and migration. Next, we identify PDZ Binding Kinase (PBK) as a novel LIN28B target. PBK is a serine/threonine kinase that promotes the proliferation and self-renewal of neural stem cells and serves as an oncogenic driver in multiple aggressive malignancies. We demonstrate that PBK is both a novel direct target of let-7i and that MYCN regulates PBK expression, thus elucidating two oncogenic drivers that converge on PBK. Functionally, PBK promotes self-renewal and migration, phenocopying LIN28B. Taken together, our findings define a role for LIN28B in neuroblastoma metastasis and define the targetable kinase PBK as a potential novel vulnerability in metastatic neuroblastoma.
| S-EPMC7186370 | biostudies-literature
Project description:The ALK(F1174L) mutation is associated with intrinsic and acquired resistance to crizotinib and cosegregates with MYCN in neuroblastoma. In this study, we generated a mouse model overexpressing ALK(F1174L) in the neural crest. Compared to ALK(F1174L) and MYCN alone, co-expression of these two oncogenes led to the development of neuroblastomas with earlier onset, higher penetrance, and enhanced lethality. ALK(F1174L)/MYCN tumors exhibited increased MYCN dosage due to ALK(F1174L)-induced activation of the PI3K/AKT/mTOR and MAPK pathways, coupled with suppression of MYCN pro-apoptotic effects. Combined treatment with the ATP-competitive mTOR inhibitor Torin2 overcame the resistance of ALK(F1174L)/MYCN tumors to crizotinib. Our findings demonstrate a pathogenic role for ALK(F1174L) in neuroblastomas overexpressing MYCN and suggest a strategy for improving targeted therapy for ALK-positive neuroblastoma.
| S-EPMC3417812 | biostudies-literature