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LIN28B alters ribosomal dynamics to promote metastasis in MYCN induced malignancy

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183351 | GEO | 2022/09/30

REPOSITORIES: GEO

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LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (Polysome sequencing)

Project description:High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we show that LIN28B expression is associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7 independent enrichment of transcripts encoding components of the translational and ribosomal apparatus, particularly those with higher adenine/uridine (AU)-content, and depletion of transcripts of neuronal developmental programs. We further show that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrate that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a post-transcriptional driver of the metastatic phenotype.

2022-09-30 | GSE183335 | GEO

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (RNA-Seq)

Project description:High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we show that LIN28B expression is associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7 independent enrichment of transcripts encoding components of the translational and ribosomal apparatus, particularly those with higher Adenine/Uridine (AU)-content, and depletion of GC-rich transcripts of neuronal developmental programs. We further show that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrate that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a post-transcriptional driver of the metastatic phenotype.

2022-09-30 | GSE158320 | GEO

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (RIP-Seq)

2022-09-30 | GSE183336 | GEO

LIN28B alters ribosomal dynamics to promote metastasis in MYCN induced malignancy

Project description:LIN28B alters ribosomal dynamics to promote metastasis in MYCN induced malignancy

| PRJNA760326 | ENA

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (RNA-Seq)

Project description:LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (RNA-Seq)

| PRJNA664805 | ENA

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (Polysome sequencing)

Project description:LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (Polysome sequencing)

| PRJNA760306 | ENA

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (RIP-Seq)

Project description:LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (RIP-Seq)

| PRJNA760307 | ENA

MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma.

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

LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis.

Project description:A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3, and itga5. Our results provide in vivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination.

| S-EPMC5605802 | biostudies-literature

LIN28B regulates transcription and potentiates MYCN-induced neuroblastoma through binding to ZNF143 at target gene promotors.

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

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