Versatility of MicroRNA Biogenesis

Volk, Naama; Shomron, Noam

doi:10.1371/journal.pone.0019391

Cited by 40 publications

(39 citation statements)

References 18 publications

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“…In addition to regulating the expression of different genes post-transcriptionally, NF90 also takes part in miRNA biogenesis. As a competitor for the association of the microprocessor complex with pri-miRNAs, NF90 usually inhibits miRNA production (27,41,42). We found that lncRNA-LET depletion resulted in elevated level of NF90 which in turn blocks miR-145 biogenesis by competitively binding to pri-miR-145 specifically.…”

Section: Discussionmentioning

confidence: 83%

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

et al. 2017

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High tumor recurrence is frequently observed in patients with urinary bladder cancers (UBCs), with the need for biomarkers of prognosis and drug response. Chemoresistance and subsequent recurrence of cancers are driven by a subpopulation of tumor initiating cells, namely cancer stem-like cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment remains largely unclear. In this study, we found that during gemcitabine treatment lncRNA-Low Expression in Tumor (lncRNA-LET) was downregulated in chemoresistant UBC, accompanied with the enrichment of CSC population. Knockdown of lncRNA-LET increased UBC cell stemness, whereas forced expression of lncRNA-LET delayed gemcitabine-induced tumor recurrence. Furthermore, lncRNA-LET was directly repressed by gemcitabine treatment-induced overactivation of TGFβ/SMAD signaling through SMAD binding element (SBE) in the lncRNA-LET promoter. Consequently, reduced lncRNA-LET increased the NF90 protein stability, which in turn repressed biogenesis of miR-145 and subsequently resulted in accumulation of CSCs evidenced by the elevated levels of stemness markers HMGA2 and KLF4. Treatment of gemcitabine resistant xenografts with LY2157299, a clinically relevant specific inhibitor of TGFβRI, sensitized them to gemcitabine and significantly reduced tumorigenecity in vivo. Notably, overexpression of TGFβ1, combined with decreased levels of lncRNA-LET and miR-145 predicted poor prognosis in UBC patients. Collectively, we proved that the dysregulated lncRNA-LET/NF90/miR-145 axis by gemcitabine-induced TGFβ1 promotes UBC chemoresistance through enhancing cancer cell stemness. The combined changes in TGFβ1/lncRNA-LET/miR-145 provide novel molecular prognostic markers in UBC outcome. Therefore, targeting this axis could be a promising therapeutic approach in treating UBC patients.

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Section: Discussionmentioning

confidence: 83%

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

et al. 2017

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“…However, the biological relevance of these changes still needs to be investigated and fully elucidated. Indeed, we have to take into account that QPCR analyses of the specific mature microRNA might be underestimated, considering that the inherent stability of the specific microRNA may be affected by cell activity and stimulation (57,58). Furthermore, the effect of DA on miR-29a regulation also may be the consequence of other molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Dopamine Inhibits the Effector Functions of Activated NK Cells via the Upregulation of the D5 Receptor

Mikulak

Bozzo

Roberto

et al. 2014

The Journal of Immunology

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Several lines of evidence indicate that dopamine (DA) plays a key role in the cross-talk between the nervous and immune systems. In this study, we disclose a novel immune-regulatory role for DA: inhibition of effector functions of activated NK lymphocytes via the selective upregulation of the D5 dopaminergic receptor in response to prolonged cell stimulation with rIL-2. Indeed, engagement of this D1-like inhibitory receptor following binding with DA suppresses NK cell proliferation and synthesis of IFN-γ. The inhibition of IFN-γ production occurs through blocking the repressor activity of the p50/c-REL dimer of the NF-κB complex. Indeed, the stimulation of the D5 receptor on rIL-2–activated NK cells inhibits the binding of p50 to the microRNA 29a promoter, thus inducing a de novo synthesis of this miRNA. In turn, the increased levels of microRNA 29a were inversely correlated with the ability of NK cells to produce IFN-γ. Taken together, our findings demonstrated that DA switches off activated NK cells, thus representing a checkpoint exerted by the nervous system to control the reactivity of these innate immune effectors in response to activation stimuli and to avoid the establishment of chronic and pathologic inflammatory processes.

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“…The choice of Drosha as a target enzyme was on the basis of the knowledge that Drosha activity is restricted to the generation of miRNAs. [25][26][27] Here, we reported that depletion of Drosha in MSCs generated EVs with a deregulation of their miRNA content and altered the intrinsic regenerative potential of MSCs and derived EVs. These data support the relevance of miRNAs shuttled by EVs in the healing properties of MSCs.…”

mentioning

confidence: 91%

AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

Collino

Bruno²,

Incarnato

et al. 2015

Journal of the American Society of Nephrology

220

227

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Phenotypic changes induced by extracellular vesicles have been implicated in mesenchymal stromal cellpromoted recovery of AKI. MicroRNAs are potential candidates for cell reprogramming toward a proregenerative phenotype. The aim of this study was to evaluate whether microRNA deregulation inhibits the regenerative potential of mesenchymal stromal cells and derived extracellular vesicles in a model of glycerol-induced AKI in severe combined immunodeficient mice. We generated mesenchymal stromal cells depleted of Drosha to alter microRNA expression. Drosha-knockdown cells produced extracellular vesicles that did not differ from those of wild-type cells in quantity, surface molecule expression, and internalization within renal tubular epithelial cells. However, these vesicles showed global downregulation of microRNAs. Whereas wild-type mesenchymal stromal cells and derived vesicles administered intravenously induced morphologic and functional recovery in AKI, the Drosha-knockdown counterparts were ineffective. RNA sequencing analysis showed that kidney genes deregulated after injury were restored by treatment with mesenchymal stromal cells and derived vesicles but not with Drosha-knockdown cells and vesicles. Gene ontology analysis showed in AKI an association of downregulated genes with fatty acid metabolism and upregulated genes with inflammation, matrix-receptor interaction, and cell adhesion molecules. These alterations reverted after treatment with wild-type mesenchymal stromal cells and extracellular vesicles but not after treatment with the Drosha-knockdown counterparts. In conclusion, microRNA depletion in mesenchymal stromal cells and extracellular vesicles significantly reduced their intrinsic regenerative potential in AKI, suggesting a critical role of microRNAs in recovery after AKI.

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Versatility of MicroRNA Biogenesis

Cited by 40 publications

References 18 publications

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

Dopamine Inhibits the Effector Functions of Activated NK Cells via the Upregulation of the D5 Receptor

AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

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