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Project description:The oncogenic transcription factor (c-)Myc is overexpressed in a variety of cancers including subtypes of B cell lymphoma. Here we study long noncoding (lnc)RNAs regulated by Myc, arguing that these lncRNAs may be involved in the very strong effect of Myc on cell proliferation. Using multiple in vitro models and taking into account the kinetics of the response to Myc as well as Myc binding sites we defined two Myc-induced and four Myc-repressed lncRNA candidates. Expression levels of the top Myc-induced lncRNA KTN1-AS1 are low in normal B cell subsets and strongly increased in multiple Myc-positive lymphoma cell lines. In addition, primary lymphoma cases stratified by high or low Myc expression show the expected KTN1-AS1 expression differences. Knockdown of KTN1-AS1 severely impaired the cell growth of multiple Burkitt lymphoma cell lines. Gene expression analysis showed that KTN1-AS1 knockdown affects >300 genes genome wide with a strong enrichment of Myc-target genes involved in metabolism and biosynthesis. In line with this finding, KTN1-AS1 depletion in B cell lymphoma cells caused a substantial decrease of Myc transcript and protein. Thus, our data indicates that KTN1-AS1 overexpression in lymphoma may reinforce high Myc expression at the transcriptional level to activate gene expression programs supporting the high metabolic rate present in lymphoma cells. In conclusion, we identified a novel positive feedback loop between c-Myc and KTN1-AS1 in B cell lymphoma cells. LncRNAs such as KTN1-AS1, that regulate important oncogenic factors in specific cell types, may open new ways to cancer therapy.
2020-04-03 | GSE119924 | GEO
Project description:shRNA-mediated Myc knockdown and shRNA-mediated knockdown of Myc-induced lncRNA KTN1-AS1 in ST486 Burkitt lymphoma cells
| PRJNA490714 | ENA
Project description:The oncogenic transcription factor (c-)Myc is overexpressed in a variety of cancers including subtypes of B cell lymphoma. Here we study long noncoding (lnc)RNAs regulated by Myc, arguing that these lncRNAs may be involved in the very strong effect of Myc on cell proliferation. Using multiple in vitro models and taking into account the kinetics of the response to Myc as well as Myc binding sites we defined two Myc-induced and four Myc-repressed lncRNA candidates. Expression levels of the top Myc-induced lncRNA KTN1-AS1 are low in normal B cell subsets and strongly increased in multiple Myc-positive lymphoma cell lines. In addition, primary lymphoma cases stratified by high or low Myc expression show the expected KTN1-AS1 expression differences. Knockdown of KTN1-AS1 severely impaired the cell growth of multiple Burkitt lymphoma cell lines. Gene expression analysis showed that KTN1-AS1 knockdown affects >300 genes genome wide with a strong enrichment of Myc-target genes involved in metabolism and biosynthesis. In line with this finding, KTN1-AS1 depletion in B cell lymphoma cells caused a substantial decrease of Myc transcript and protein. Thus, our data indicates that KTN1-AS1 overexpression in lymphoma may reinforce high Myc expression at the transcriptional level to activate gene expression programs supporting the high metabolic rate present in lymphoma cells. In conclusion, we identified a novel positive feedback loop between c-Myc and KTN1-AS1 in B cell lymphoma cells. LncRNAs such as KTN1-AS1, that regulate important oncogenic factors in specific cell types, may open new ways to cancer therapy.
2020-04-03 | GSE119923 | GEO
Project description:Gene expression analysis after shRNA-mediated knockdown of Myc-induced lncRNA KTN1-AS1 in ST486 Burkitt lymphoma cells
| PRJNA490718 | ENA
Project description:Expression analysis of mRNA and lncRNA expression levels after shRNA-mediated Myc knockdown in ST486 Burkitt lymphoma cells
| PRJNA490717 | ENA
Project description:Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.
| S-EPMC4586867 | biostudies-literature
Project description:BackgroundLncRNA PCED1B-AS1 (PCED1B-AS1) promotes glioma. This study aimed to investigate its role in osteosarcoma (OS).MethodsThe study included 60 OS patients. Accumulation of miR-10a and PCED1B-AS1 in tissues from OS patients and cell lines was determined by RT-qPCR. Cell transfections were performed for interaction analysis. Participation of PCED1B-AS1 siRNA silencing and miR-10a overexpression in proliferation, invasion, and migration of U2OS and MG-63 cells was analyzed by cell proliferation assay and Transwell assay.ResultsPCED1B-AS1 level was increased in OS and positively correlated with miR-10a level. In OS cells, PCED1B-AS1 siRNA silencing downregulated miR-10a. Methylation-specific PCR analysis showed that PCED1B-AS1 siRNA silencing decreased the methylation of miR-10a gene promoter. Moreover, PCED1B-AS1 siRNA silencing suppressed OS cell proliferation, invasion, and migration. In addition, miR-10a overexpression attenuated the effects of PCED1B-AS1 siRNA silencing.ConclusionPCED1B-AS1 knockdown may inhibit OS cell proliferation and movement by regulating miR-10 gene methylation.
| S-EPMC9590122 | biostudies-literature
Project description:BackgroundThe oncogenic transcription factor MYC is pathologically activated in many human malignancies. A paradigm for MYC dysregulation is offered by Burkitt lymphoma, where chromosomal translocations leading to Immunoglobulin gene-MYC fusion are the crucial initiating oncogenic events. However, Burkitt lymphoma cases with no detectable MYC rearrangement but maintaining MYC expression have been identified and alternative mechanisms can be involved in MYC dysregulation in these cases.MethodsWe studied the microRNA profile of MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases in order to uncover possible differences at the molecular level. Data was validated at the mRNA and protein level by quantitative Real-Time polymerase chain reaction and immunohistochemistry, respectively.ResultsWe identified four microRNAs differentially expressed between the two groups. The impact of these microRNAs on the expression of selected genes was then investigated. Interestingly, in MYC translocation-negative cases we found over-expression of DNA-methyl transferase family members, consistent to hypo-expression of the hsa-miR-29 family. This finding suggests an alternative way for the activation of lymphomagenesis in these cases, based on global changes in methylation landscape, aberrant DNA hypermethylation, lack of epigenetic control on transcription of targeted genes, and increase of genomic instability. In addition, we observed an over-expression of another MYC family gene member, MYCN that may therefore represent a cooperating mechanism of MYC in driving the malignant transformation in those cases lacking an identifiable MYC translocation but expressing the gene at the mRNA and protein levels.ConclusionsCollectively, our results showed that MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases are slightly different in terms of microRNA and gene expression. MYC translocation-negative Burkitt lymphoma, similarly to other aggressive B-cell non Hodgkin's lymphomas, may represent a model to understand the intricate molecular pathway responsible for MYC dysregulation in cancer.
| S-EPMC4600215 | biostudies-literature
Project description:ObjectivesThe latest revision of lymphoma's World Health Organization classification describes the new provisional entity "Burkitt-like lymphoma with 11q aberration" (BLL, 11q) as lacking MYC rearrangement, but harboring the specific11q-gain/loss aberration. We report genetic characteristics of 11 lymphoma cases with this aberration.MethodsClassical cytogenetics, fluorescence in situ hybridization (FISH), and single nucleotide polymorphism/array comparative genomic hybridization.ResultsThe 11q aberrations were described as duplication, inversion, and deletion. Array comparative genomic hybridization showed two types of duplication: bigger than 50 megabase pairs (Mbp) and smaller than 20 Mbp, which were associated with bulky tumor larger than 20 cm and amplification of the 11q23.3 region, including KMT2A. Six cases revealed a normal FISH status of MYC and were diagnosed as BLL,11q. Five cases showed MYC rearrangement and were diagnosed as Burkitt lymphoma (BL) or high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS).ConclusionsThe 11q-gain/loss is not specific for BLL, 11q, but occurs recurrently in MYC-positive BL and MYC-positive HGBL.
| S-EPMC5848380 | biostudies-literature
Project description:Burkitt lymphoma (BL) is an aggressive B-cell lymphoma, with a characteristic clinical presentation, morphology and immunophenotype. Over the past years, the typical translocation t(8;14) and its variants have been considered the molecular hallmark of this tumor. However, BL cases with no detectable MYC rearrangement have been identified. Intriguingly, these cases express MYC at levels comparable with cases carrying the translocation. In normal cells c-Myc expression is tightly regulated through a complex feedback loop mechanism. In cancer, MYC is often dysregulated, commonly due to genomic abnormalities. It has recently emerged that this phenomenon may rely on an alteration of post-transcriptional regulation mediated by microRNAs (miRNAs), whose functional alterations are associated with neoplastic transformation. It is also emerging that c-Myc modulates miRNA expression, revealing an intriguing crosstalk between c-Myc and miRNAs. Here, we investigated the expression of miRNAs possibly regulated by c-Myc in BL cases positive or negative for the translocation. A common trend of miRNA expression, with the exception of hsa-miR-9*, was observed in all of the cases. Intriguingly, down-regulation of this miRNA seems to specifically identify a particular subset of BL cases, lacking MYC translocation. Here, we provided evidence that hsa-miR-9-1 gene is heavily methylated in those cases. Finally, we showed that hsa-miR-9* is able to modulate E2F1 and c-Myc expression. Particularly, this study identifies hsa-miR-9* as potentially relevant for malignant transformation in BL cases with no detectable MYC translocation. Deregulation of hsa-miR-9* may therefore be useful as a diagnostic tool, suggesting it as a promising novel candidate for tumor cell marker.
| S-EPMC2945769 | biostudies-literature