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MiR-146b-5p regulates IL-23 receptor complex expression in chronic lymphocytic leukemia cells.

ABSTRACT: Chronic lymphocytic leukemia (CLL) cells express the interleukin-23 receptor (IL-23R) chain, but the expression of the complementary IL-12Rβ1 chain requires cell stimulation via surface CD40 molecules (and not via the B-cell receptor [BCR]). This stimulation induces the expression of a heterodimeric functional IL-23R complex and the secretion of IL-23, initiating an autocrine loop that drives leukemic cell expansion. Based on the observation in 224 untreated Binet stage A patients that the cases with the lowest miR-146b-5p concentrations had the shortest time to first treatment (TTFT), we hypothesized that miR-146b-5p could negatively regulate IL-12Rβ1 side chain expression and clonal expansion. Indeed, miR-146b-5p significantly bound to the 3'-UTR region of the IL-12Rβ1 mRNA in an in vitro luciferase assay. Downregulation of miR-146b-5p with specific miRNA inhibitors in vitro led to the upregulation of the IL-12Rβ1 side chain and expression of a functional IL-23R complex similar to that observed after stimulation of the CLL cell through the surface CD40 molecules. Expression of miR-146b-5p with miRNA mimics in vitro inhibited the expression of the IL-23R complex after stimulation with CD40L. Administration of a miR-146b-5p mimic to NSG mice, successfully engrafted with CLL cells, caused tumor shrinkage, with a reduction of leukemic nodules and of IL-12Rβ1-positive CLL cells in the spleen. Our findings indicate that IL-12Rβ1 expression, a crucial checkpoint for the functioning of the IL-23 and IL-23R complex loop, is under the control of miR-146b-5p, which may represent a potential target for therapy since it contributes to the CLL pathogenesis. This trial is registered at www.clinicaltrials.gov as NCT00917540.

SUBMITTER: Matis S

PROVIDER: S-EPMC9647700 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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MiR-146b-5p regulates IL-23 receptor complex expression in chronic lymphocytic leukemia cells.

Matis Serena S Grazia Recchia Anna A Colombo Monica M Cardillo Martina M Fabbi Marina M Todoerti Katia K Bossio Sabrina S Fabris Sonia S Cancila Valeria V Massara Rosanna R Reverberi Daniele D Emionite Laura L Cilli Michele M Cerruti Giannamaria G Salvi Sandra S Bet Paola P Pigozzi Simona S Fiocca Roberto R Ibatici Adalberto A Angelucci Emanuele E Gentile Massimo M Monti Paola P Menichini Paola P Fronza Gilberto G Torricelli Federica F Ciarrocchi Alessia A Neri Antonino A Fais Franco F Tripodo Claudio C Morabito Fortunato F Ferrarini Manlio M Cutrona Giovanna G

Blood advances 20221001 20

Chronic lymphocytic leukemia (CLL) cells express the interleukin-23 receptor (IL-23R) chain, but the expression of the complementary IL-12Rβ1 chain requires cell stimulation via surface CD40 molecules (and not via the B-cell receptor [BCR]). This stimulation induces the expression of a heterodimeric functional IL-23R complex and the secretion of IL-23, initiating an autocrine loop that drives leukemic cell expansion. Based on the observation in 224 untreated Binet stage A patients that the cases ...[more]

PMID: 35819446

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Project description:BackgroundNDRG2 is identified as a tumor suppressor gene in many tumors, and functions in cell proliferation, differentiation and apoptosis. Recent data indicate that NDRG2 expression is up-regulated by TP53. Moreover, proposed mechanisms of NDRG2 inactivation include epigenetic silencing of the NDRG2 promoter and down-regulation by microRNAs (miRNAs). However, few studies have ever been done on the role of NDRG2 and the NDRG2-regulating miRNAs interference in chronic lymphocytic leukemia (CLL).MethodsNDRG2 and microRNAs mRNA levels in CLL subjects were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay was performed to determine NDRG2-related miRNAs. Low expression of mature exogenous miRNAs in CLL cells was established by transient transfection. NDRG2 protein levels in CLL cells were detected by western blot. In addition, flow cytometry was conducted to examine the apoptosis of CLL cells.ResultsLower expression of NDRG2 was found in the B-cells from 102 CLL patients compared the 40 normal subjects (P < 0.001). Patients with advanced Binet stage (P = 0.001), high lactate dehydrogenase (LDH) level (P = 0.036), un-mutated immunoglobulin heavy chain variable region gene (IGHV) (P = 0.004) and those with p53 aberrations (P < 0.001) had a markedly lower levels of NDRG2 mRNA. This decrease was associated with briefer time-to-treatment (P = 0.001) and poorer survival (P < 0.001). High expression of miR-28-5p and miR-650 was associated with Binet B/C stage (P = 0.044) and IGHV un-mutated (P = 0.011), as well as Binet B/C stage (P = 0.013) and p53 aberrations (P = 0.037), respectively. Inhibition of miR-28-5p or miR-650 could induce more apoptosis in CLL cells with germline TP53.ConclusionsNDRG2 mRNA levels might be a useful prognostic variable for patients of CLL and up-regulating NDRG2 transcription may be a therapy approach in CLL without p53 aberrations.

Project description:ObjectiveCircular RNAs (circRNAs) play a critical role in the modulation of tumor metabolism. However, the expression patterns and metabolic function of circRNAs in chronic lymphocytic leukemia (CLL) remain largely unknown. This study aimed to elucidate the role of circRNAs in the lipid metabolism of CLL.MethodsThe expression and metabolic patterns of circRNAs in a cohort of 53 patients with CLL were investigated using whole transcriptome sequencing. Cell viability, liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis, lipid analysis, Nile red staining as well as triglyceride (TG) assay were used to evaluate the biological function of circRIC8B in CLL. The regulatory mechanisms of circRIC8B/miR-199b-5p/lipoprotein lipase (LPL) axis were explored by luciferase assay, RNA immunoprecipitation (RIP), qRT-PCR, and fluorescence in situ hybridization (FISH). CCK-8 and flow cytometry were used to verify the inhibition role of cholesterol absorption inhibitor, ezetimibe, in CLL cells.ResultsIncreased circRIC8B expression was positively correlated with advanced progression and poor prognosis. Knockdown of circRIC8B significantly suppressed the proliferation and lipid accumulation of CLL cells. In contrast, the upregulation of circRIC8B exerted opposite effects. Mechanistically, circRIC8B acted as a sponge of miR-199b-5p and prevented it from decreasing the level of LPL mRNA, and this promotes lipid metabolism alteration and facilitates the progression of CLL. What's more, ezetimibe suppressed the expression of LPL mRNA and inhibited the growth of CLL cells.ConclusionsIn this study, the expressional and metabolic patterns of circRNAs in CLL was illustrated for the 1st time. Our findings revealed that circRIC8B regulates the lipid metabolism abnormalities in and development of CLL through the miR-199b-5p/LPL axis. CircRIC8B may serve as a promising prognostic marker and therapeutic target, which enhances the sensitivity to ezetimibe in CLL.

Dataset Information

MiR-146b-5p regulates IL-23 receptor complex expression in chronic lymphocytic leukemia cells.

Publications

MiR-146b-5p regulates IL-23 receptor complex expression in chronic lymphocytic leukemia cells.

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