Dataset Information

The Expression of the Cancer-Associated lncRNA Snhg15 Is Modulated by EphrinA5-Induced Signaling.

ABSTRACT: The Eph receptor tyrosine kinases and their respective ephrin-ligands are an important family of membrane receptors, being involved in developmental processes such as proliferation, migration, and in the formation of brain cancer such as glioma. Intracellular signaling pathways, which are activated by Eph receptor signaling, are well characterized. In contrast, it is unknown so far whether ephrins modulate the expression of lncRNAs, which would enable the transduction of environmental stimuli into our genome through a great gene regulatory spectrum. Applying a combination of functional in vitro assays, RNA sequencing, and qPCR analysis, we found that the proliferation and migration promoting stimulation of mouse cerebellar granule cells (CB) with ephrinA5 diminishes the expression of the cancer-related lncRNA Snhg15. In a human medulloblastoma cell line (DAOY) ephrinA5 stimulation similarly reduced SNHG15 expression. Computational analysis identified triple-helix-mediated DNA-binding sites of Snhg15 in promoters of genes found up-regulated upon ephrinA5 stimulation and known to be involved in tumorigenic processes. Our findings propose a crucial role of Snhg15 downstream of ephrinA5-induced signaling in regulating gene transcription in the nucleus. These findings could be potentially relevant for the regulation of tumorigenic processes in the context of glioma.

SUBMITTER: Pensold D

PROVIDER: S-EPMC7866228 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The Expression of the Cancer-Associated lncRNA <i>Snhg15</i> Is Modulated by EphrinA5-Induced Signaling.

Pensold Daniel D Gehrmann Julia J Pitschelatow Georg G Walberg Asa A Braunsteffer Kai K Reichard Julia J Ravaei Amin A Linde Jenice J Lampert Angelika A Costa Ivan G IG Zimmer-Bensch Geraldine G

International journal of molecular sciences 20210129 3

The Eph receptor tyrosine kinases and their respective ephrin-ligands are an important family of membrane receptors, being involved in developmental processes such as proliferation, migration, and in the formation of brain cancer such as glioma. Intracellular signaling pathways, which are activated by Eph receptor signaling, are well characterized. In contrast, it is unknown so far whether ephrins modulate the expression of lncRNAs, which would enable the transduction of environmental stimuli in ...[more]

PMID: 33572758

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Project description:BackgroundTo our knowledge, LncRNA SNHG15 exerted its tumor-promoting effects to facilitate the development of breast cancer (BC), but there still needed more data to elucidate the potential underlying mechanisms.MethodsWe examined genes expression status by performing Real-Time qPCR and Western Blot analysis, and cellular functions, including cell proliferation, viability, apoptosis, mobility, were measured by using the CCK-8 assay, colony formation assay, trypan blue staining assay, flow cytometer (FCM), transwell assay and wound scratch assay, respectively. The predicted targeting sites in LncRNA SNHG15, miR-451 and c-Myc 3'UTR were validated by dual-luciferase reporter gene system assay. Finally, we established the tumor-bearing mice models, and the expression status, including its enrichment and cellular localization were examined by immunohistochemistry (IHC) assay.ResultsOur data indicated LncRNA SNHG15 upregulated c-Myc to facilitate BC progression by sponging miR-451 in a competing endogenous RNA (ceRNA)-dependent manner in vitro and in vivo. Specifically, LncRNA SNHG15 and c-Myc were upregulated, while miR-451 was downregulated in BC cells and clinical tissues, compared to their normal counterparts. In addition, miR-451 negatively correlated with LncRNA SNHG15 and c-Myc, and LncRNA SNHG15 was positively relevant to c-Myc in BC tissues. Next, we validated that LncRNA SNHG15 sponged miR-451 to upregulate c-Myc in BC cells. Further gain- and loss-of-function experiments evidenced that LncRNA SNHG15 promoted, while miR-451 inhibited malignant phenotypes, including cell proliferation, viability, migration, invasion and epithelial-mesenchymal transition (EMT) in BC cells. Interestingly, the inhibiting effects of LncRNA SNHG15 ablation on BC progression were abrogated by both silencing miR-451 and overexpressing c-Myc.ConclusionsWe concluded that targeting the LncRNA SNHG15/miR-451/c-Myc signaling cascade was novel to hamper BC progression, which broadened our knowledge in this field, and provided potential biomarkers for BC diagnosis and treatment.

Project description:BackgroundAccumulating evidence demonstrates the oncogenic roles of lncRNA (long non-coding RNA) molecules in a wide variety of cancer types including glioma. Equally important, However, tumorigenic functions of lncRNA in glioma remain largely unclear. A recent study suggested lncRNA SNHG15 played a role for regulating angiogenesis in glioma but its role in the tumor microenvironment (TME) was not investigated.MethodsFirst, we showed that SNHG15 was upregulated in GBM cells and associated with a poor prognosis for the patients of GBM using public databases. Next, we collected temozolomide sensitive (TMZ-S) and resistant (TMZ-R) clinical samples and demonstrated that co-culturing TMZ-R cells with HMC3 (microglial) cells promoted M2-polarization of HMC3 and the secretion of pro-GBM cytokines TGF-β and IL-6.ResultsComparative qPCR analysis of TMZ-S and TMZ-R cells showed that a significantly higher level of SNHG15, coincidental with a higher level of Sox2, β-catenin, EGFR, and CDK6 in TMZ-R cells. Subsequently, using bioinformatics tool, a potential mechanistic route for SNHG15 to promote GBM tumorigenesis was by inhibiting tumor suppressor, miR-627-5p which leads to activation of CDK6. Gene-silencing technique was employed to demonstrate that suppression of SNHG15 indeed led to the suppression of GBM tumorigenesis, accompanied by an increase miR-627-5p and decreased its two oncogenic targets, CDK6 and SOX-2. In addition, SNHG15-silenced TMZ-R cells became significantly sensitive towards TMZ treatment and less capable of promoting M2-phenotype in the HMC3 microglial cells. We then evaluated the potential anti-GBM activity of CDK6 inhibitor, palbociclib, using TMZ-R PDX mouse models. Palbociclib treatment significantly reduced tumorigenesis in TMZ-R/HMC3 bearing mice and SNHG15 and CDK6 expression was significantly reduced while miR-627-5p level was increased. Additionally, palbociclib treatment appeared to overcome TMZ resistance as well as reduced M2 markers in HMC3 cells.ConclusionTogether, we provided evidence supporting the usage of CDK6 inhibitor for TMZ-resistant GBM cases. Further investigation is warranted for the consideration of clinical trials.

Dataset Information

The Expression of the Cancer-Associated lncRNA Snhg15 Is Modulated by EphrinA5-Induced Signaling.

Publications

The Expression of the Cancer-Associated lncRNA <i>Snhg15</i> Is Modulated by EphrinA5-Induced Signaling.

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