Background and Aims: HCV chronic infection is closely related to the development of lymphoproliferative disorders (LPDs), mainly mixed cryoglobulinemia (MC) and some subtypes of B-cell lymphoma. The pathogenesis of HCV-LPDs is still largely unknown. Modification of the expression levels of specific microRNAs (miRNAs) has been associated with different autoimmune and/or LPDs. In particular, the endogenous miR-17/92 cluster is very often amplified in cancer and in autoimmunity. Scarce data exist about the modifications of miRNA expression levels in HCV-related LPDs. The aim of this study was to evaluate the modifications of the expression levels of the miR-17/92 cluster in a large population of HCV patients with and without MC and the effects of viral eradication. Methods: The expression levels of miR-17/92 cluster were evaluated by Real Time PCR in PBMC samples from 79 HCV patients: 34 without LPD [HCV] and 45 with MC [HCV-MC]; among the 45 MC patients were included 20 patients who experienced a sustained virological and clinical response after antiviral treatment and of which pre and post therapy sampling was available. Relative expression levels of all the members of the miR-17/92 cluster (namely, miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a) were evaluated with the 2-DDCt method, using miR-let-7d as housekeeping. Results: All the members of the miR-17/92 cluster were highly upregulated in PBMCs from HCV-MC patients (p < 0.001) when compared to HCV group. A restoration of miRNAs levels was observed in the samples taken after viral eradication (miR-17, miR-18a, miR-19a, miR-19b, miR-20a, p < 0.001 and miR-92a, p < 0.05, when compared with pre-treatment levels). Regarding miR-20a, the levels in samples taken after HCV eradication continued to be significantly higher than in controls (HCV patients) (p < 0.05), in spite of the sudden fall observed after therapy. Conclusions: This study, for the first time, shows that the expression pattern of miRNA-17/92 cluster is modified in PBMC from HCV patients with MC. The sudden restoration of these values of expression in patients achieving a sustained virological and clinical response after antiviral treatment, strongly suggests that miR-17/92 cluster plays a key role in the pathogenesis of MC.

MIR-17/92 EXPRESSION PATTERN: A MOLECULAR SIGNATURE OF HCV-RELATED MIXED CRYOGLOBULINEMIA

Gragnani L;
2015-01-01

Abstract

Background and Aims: HCV chronic infection is closely related to the development of lymphoproliferative disorders (LPDs), mainly mixed cryoglobulinemia (MC) and some subtypes of B-cell lymphoma. The pathogenesis of HCV-LPDs is still largely unknown. Modification of the expression levels of specific microRNAs (miRNAs) has been associated with different autoimmune and/or LPDs. In particular, the endogenous miR-17/92 cluster is very often amplified in cancer and in autoimmunity. Scarce data exist about the modifications of miRNA expression levels in HCV-related LPDs. The aim of this study was to evaluate the modifications of the expression levels of the miR-17/92 cluster in a large population of HCV patients with and without MC and the effects of viral eradication. Methods: The expression levels of miR-17/92 cluster were evaluated by Real Time PCR in PBMC samples from 79 HCV patients: 34 without LPD [HCV] and 45 with MC [HCV-MC]; among the 45 MC patients were included 20 patients who experienced a sustained virological and clinical response after antiviral treatment and of which pre and post therapy sampling was available. Relative expression levels of all the members of the miR-17/92 cluster (namely, miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a) were evaluated with the 2-DDCt method, using miR-let-7d as housekeeping. Results: All the members of the miR-17/92 cluster were highly upregulated in PBMCs from HCV-MC patients (p < 0.001) when compared to HCV group. A restoration of miRNAs levels was observed in the samples taken after viral eradication (miR-17, miR-18a, miR-19a, miR-19b, miR-20a, p < 0.001 and miR-92a, p < 0.05, when compared with pre-treatment levels). Regarding miR-20a, the levels in samples taken after HCV eradication continued to be significantly higher than in controls (HCV patients) (p < 0.05), in spite of the sudden fall observed after therapy. Conclusions: This study, for the first time, shows that the expression pattern of miRNA-17/92 cluster is modified in PBMC from HCV patients with MC. The sudden restoration of these values of expression in patients achieving a sustained virological and clinical response after antiviral treatment, strongly suggests that miR-17/92 cluster plays a key role in the pathogenesis of MC.
https://www.sciencedirect.com/science/article/pii/S016882781530074X
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1163428
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