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The long non-coding RNA CRNDE regulates growth of multiple myeloma cells via an effect on IL6 signalling.

ABSTRACT: Multiple myeloma (MM) is a currently incurable malignancy of antibody-secreting plasma cells. Long non-coding RNAs (lncRNAs) have been recognised as an important class of regulatory molecules which are increasingly implicated in tumorigenesis. While recent studies have demonstrated changes in expression of lncRNAs in MM, the functional significance and molecular pathways downstream of these changes remain poorly characterised. In this study, we have performed CRISPR-mediated deletion of the locus encoding the lncRNA Colorectal Neoplasia Differentially Expressed (CRNDE), a known oncogenic lncRNA that is overexpressed in plasma cells of MM patients and is a marker of poor prognosis. We found that CRISPR-mediated deletion of the CRNDE locus in MM cells decreases proliferation and adhesion properties, increases sensitivity to Dexamethasone and reduces tumour growth in an in vivo xenograft model. Transcriptomic profiling in CRNDE-deleted MM cells demonstrated that CRNDE activates expression of a number of genes previously implicated in the aetiology of MM, including IL6R. We further demonstrate that deletion of the CRNDE locus diminishes IL6 signalling and proliferative responses in MM cells. Altogether this study reveals the IL6 signalling pathway as a novel mechanism by which CRNDE impacts upon MM cell growth and disease progression.

SUBMITTER: David A

PROVIDER: S-EPMC8179846 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Correction to: The long non-coding RNA CRNDE regulates growth of multiple myeloma cells via an effect on IL6 signaling.

Project description: Not available

| S-EPMC8414794 | biostudies-literature

CRNDE: an oncogenic long non-coding RNA in cancers.

Project description:Colorectal neoplasia differentially expressed (CRNDE) is a long non-coding RNA which has been proved upregulated in various cancers. Meanwhile, CRNDE has been demonstrated to be involved in multiple biological processes of different cancers according to previous study. Moreover, recent studies suggested CRNDE might be a potential diagnostic biomarker and prognostic predictor due to its high sensitivity and specificity in cancer tissues and plasma. In this review, we summarize the biological function of CRNDE and the relevant mechanisms in cancers to establish a molecular basis for the clinical use of CRNDE in the future.

| S-EPMC7218640 | biostudies-literature

Long non-coding RNA-CRNDE: a novel regulator of tumor growth and angiogenesis in hepatoblastoma.

Project description:Long non-coding RNAs (lncRNAs) are involved in many biological processes, such as angiogenesis, invasion, cell proliferation, and apoptosis. They have emerged as key players in the pathology of several tumors, including hepatoblastoma. In this study, we elucidate the biological and clinical significance of CRNDE up-regulation in hepatoblastoma. CRNDE is significantly up-regulated in human hepatoblastoma specimens and metastatic hepatoblastoma cell lines. CRNDE knockdown reduces tumor growth and tumor angiogenesis in vivo, and decreases hepatoblastoma cell viability, proliferation, and angiogenic effect in vitro. Mechanistic studies show that CRNDE knockdown plays its anti-proliferation and anti-angiogenesis role via regulating mammalian target of rapamycin (mTOR) signaling. Taken together, this study reveals a crucial role of CRNDE in the pathology of hepatoblastoma. CRNDE may serve as a promising diagnostic marker and therapeutic target for hepatoblastoma.

| S-EPMC5522051 | biostudies-other

Knockdown of long non-coding RNA H19 inhibits multiple myeloma cell growth via NF-?B pathway.

Project description:Long non-coding RNAs (lncRNAs) are implicated in the complex network of cancer including Multiple myeloma (MM) and play important roles in tumor development. lncH19 was significantly up-regulated in multiple cancer types, suggesting it is a potential oncogene. However, the exact functions and downstream mechanisms are largely unknown. This study aimed to investigate whether H19 participates in the cell growth of MM and elucidate the underlying mechanism. We found that H19 was abnormally overexpressed in MM cell lines and sorted CD138+ MM bone marrow tissues. H19 knockdown induced by shRNA transfection significantly inhibited proliferation, viability and colony formation in MM cells, as well as inactivated NF-?B pathway. Moreover, combination treatment of H19 knockdown and NF-?B suppression (induced by specific inhibitor PDTC) produced synergistically inhibitory effects. Bone marrow expression of H19 was positively associated with circulating IL-6 or IL-8 level in the same MM patients. And patients with high expression of H19 had a lower survival rate. Taken together, we confirmed the abnormal upregulation of a novel lncRNA, H19, in human MM. H19 was involved in MM cell growth. The linkage between H19 and NF-?B pathway may provide a novel interpretation for the mechanism of H19's growth regulation in MM.

| S-EPMC5741752 | biostudies-literature

Impact of the long non-coding RNA CRNDE on the transcriptome of the multiple myeloma cell line KMS11

Project description:Multiple myeloma (MM) is a currently incurable malignancy of antibody-secreting plasma cells. Long non-coding RNAs (lncRNAs) have been recognised as an important class of regulatory molecules which are increasingly implicated in tumorigenesis. While recent studies have demonstrated changes in expression of lncRNAs in MM, the functional significance and molecular pathways downstream of these changes remain poorly characterised. In this study we have performed CRISPR-mediated deletion of the locus encoding the lncRNA Colorectal Neoplasia Differentially Expressed (CRNDE), a known oncogenic lncRNA that is overexpressed in plasma cells of MM patients and is a marker of poor prognosis. We found that CRISPR-mediated deletion of the CRNDE locus in MM cells decreases proliferation and adhesion properties, increases sensitivity to Dexamethasone and reduces tumour growth in an in vivo xenograft model. Transcriptomic profiling in CRNDE-deleted MM cells demonstrated that CRNDE activates expression of a number of genes previously implicated in the aetiology of MM, including IL6R. We further demonstrate that deletion of the CRNDE locus diminishes IL6 signalling and proliferative responses in MM cells. Altogether this study reveals the IL6 signalling pathway as a novel mechanism by which CRNDE impacts upon MM cell growth and disease progression.

2020-09-04 | GSE155091 | GEO

CRNDE: A Long Non-Coding RNA Involved in CanceR, Neurobiology, and DEvelopment.

Project description:CRNDE is the gene symbol for Colorectal Neoplasia Differentially Expressed (non-protein-coding), a long non-coding RNA (lncRNA) gene that expresses multiple splice variants and displays a very tissue-specific pattern of expression. CRNDE was initially identified as a lncRNA whose expression is highly elevated in colorectal cancer, but it is also upregulated in many other solid tumors and in leukemias. Indeed, CRNDE is the most upregulated lncRNA in gliomas and here, as in other cancers, it is associated with a "stemness" signature. CRNDE is expressed in specific regions within the human and mouse brain; the mouse ortholog is high in induced pluripotent stem cells and increases further during neuronal differentiation. We suggest that CRNDE is a multifunctional lncRNA whose different splice forms provide specific functional scaffolds for regulatory complexes, such as the polycomb repressive complex 2 (PRC2) and CoREST chromatin-modifying complexes, which CRNDE helps pilot to target genes.

| S-EPMC3509318 | biostudies-literature

Epigenetic silencing of long non-coding RNA BM742401 in multiple myeloma: impact on prognosis and myeloma dissemination.

Project description:Background:Long non-coding RNA (lncRNA) BM742401 is a tumor suppressor in gastric cancer and chronic lymphocytic leukemia. As the promoter and coding region of BM742401 are fully embedded in a CpG island, we hypothesized that BM742401 is a tumor suppressor lncRNA epigenetically silenced by promoter DNA methylation in multiple myeloma. Methods:Methylation-specific PCR and quantitative bisulfite pyrosequencing were performed to detect the methylation of BM742401 in normal plasma cells, myeloma cell lines and primary myeloma samples. The expression of BM742401 was measured by qRT-PCR. The function of BM742401 in multiple myeloma cells was analyzed by lentivirus transduction followed by migration assay. Results:BM742401 methylation was detected in 10 (66.7%) myeloma cell lines but not normal plasma cells, and inversely correlated with expression of BM742401. In primary samples, BM742401 methylation was detected in 3 (12.5%) monoclonal gammopathy of undetermined significance, 9 (15.8%) myeloma at diagnosis and 8 (17.0%) myeloma at relapse/progression. Moreover, BM742401 methylation at diagnosis was associated with inferior overall survival (median OS: 25 vs. 39 months; P?=?0.0496). In myeloma cell line JJN-3, stable overexpression of BM742401 by lentivirus transduction resulted in reduced cell migration (P?=?0.0001) but not impacting cell death or proliferation. Conclusions:This is the first report of tumor-specific methylation-mediated silencing of BM742401 in myeloma, which is likely an early event in myelomagenesis with adverse impact on overall survival. Moreover, BM742401 is a tumor suppressor lncRNA by inhibiting myeloma cell migration, hence implicated in myeloma plasma cell homing, metastasis and disease progression.

| S-EPMC7446116 | biostudies-literature

In Silico Characterization of miRNA and Long Non-Coding RNA Interplay in Multiple Myeloma.

Project description:The identification of deregulated microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in multiple myeloma (MM) has progressively added a further level of complexity to MM biology. In addition, the cross-regulation between lncRNAs and miRNAs has begun to emerge, and theoretical and experimental studies have demonstrated the competing endogenous RNA (ceRNA) activity of lncRNAs as natural miRNA decoys in pathophysiological conditions, including cancer. Currently, information concerning lncRNA and miRNA interplay in MM is virtually absent. Herein, we investigated in silico the lncRNA and miRNA relationship in a representative datasets encompassing 95 MM and 30 plasma cell leukemia patients at diagnosis and in four normal controls, whose expression profiles were generated by a custom annotation pipeline to detect specific lncRNAs. We applied target prediction analysis based on miRanda and RNA22 algorithms to 235 lncRNAs and 459 miRNAs selected with a potential pivotal role in the pathology of MM. Among pairs that showed a significant correlation between lncRNA and miRNA expression levels, we identified 11 lncRNA-miRNA relationships suggestive of a novel ceRNA network with relevance in MM.

| S-EPMC5192483 | biostudies-literature

Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling.

Project description:AimsLong non-coding RNAs (lncRNAs) have been shown to regulate numerous processes in the human genome, but the function of these transcripts in vascular aging is largely unknown. We aim to characterize the expression of lncRNAs in endothelial aging and analyse the function of the highly conserved lncRNA H19.Methods and resultsH19 was downregulated in endothelium of aged mice. In human, atherosclerotic plaques H19 was mainly expressed by endothelial cells and H19 was significantly reduced in comparison to healthy carotid artery biopsies. Loss of H19 led to an upregulation of p16 and p21, reduced proliferation and increased senescence in vitro. Depletion of H19 in aortic rings of young mice inhibited sprouting capacity. We generated endothelial-specific inducible H19 deficient mice (H19iEC-KO), resulting in increased systolic blood pressure compared with control littermates (Ctrl). These H19iEC-KO and Ctrl mice were subjected to hindlimb ischaemia, which showed reduced capillary density in H19iEC-KO mice. Mechanistically, exon array analysis revealed an involvement of H19 in IL-6 signalling. Accordingly, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were upregulated upon H19 depletion. A luciferase reporter screen for differential transcription factor activity revealed STAT3 as being induced upon H19 depletion and repressed after H19 overexpression. Furthermore, depletion of H19 increased the phosphorylation of STAT3 at TYR705 and pharmacological inhibition of STAT3 activation abolished the effects of H19 silencing on p21 and vascular cell adhesion molecule 1 expression as well as proliferation.ConclusionThese data reveal a pivotal role for the lncRNA H19 in controlling endothelial cell aging.

| S-EPMC6302267 | biostudies-literature

MicroRNA miR-188-5p as a mediator of long non-coding RNA MALAT1 regulates cell proliferation and apoptosis in multiple myeloma.

Project description:Multiple myeloma (MM), a malignancy of plasma cells mainly derived from the bone marrow, has remained incurable generally. LncRNA MALAT1 has been reported to be upregulated in the MM cells and knockdown of MALAT1 inhibited MM cell cycle progression and enhanced cell apoptosis. Online target prediction showed that two target sites for MALAT1 existed in miR-188-5p, which has been identified as a tumor suppressor in other types of cancers. However, the role of miR-188-5p in the MM and whether miR-188-5p mediates the MM tumor progression regulated by MALAT1 are still unknown. Herein, four main MM cell lines were adopted to investigate the effects of miR-188-5p on cell proliferation and apoptosis via transfection with miR-188-5p mimic/inhibitor and co-transfection with miR-188-5p inhibitor and MALAT1-shRNA plasmids. Xenograft tumor model was also established to study these effects in vivo. Overexpression of miR-188-5p inhibited cell viability, cell proliferation as well as tumor growth and arrested cell cycle at G1 to S transition, but miR-188-5p knockdown showed opposite effects on the MM cells in vitro and in vivo. Moreover, MALAT1 was shown to be inversely correlated with miR-188-5p expression through direct binding to miR-188-5p, and in turn, miR-188-5p could mediate the MM cell proliferation and apoptosis regulated by MALAT1. These findings indicate that miR-188-5p serves as a tumor suppressor in the progression of the MM and is directly involved in MM cell proliferation and apoptosis regulated by MALAT1, which may provide a potential therapeutic target or prognostic indictor for MM clinical treatment.

| S-EPMC8806342 | biostudies-literature

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