Hepatitis C-associated B-cell non-Hodgkin lymphomas: The emerging role of miRNA-26b
Authors: Laura Gragnani, Elisa Fognani, Alessia Piluso, Anna Linda Zignego
Journal: Journal of Hepatology (2013)

Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical managementJournal of HepatologyVol. 59Issue 1PreviewThere is ample epidemiologic evidence for an association of chronic hepatitis C virus (HCV) infection with B-cell non-Hodgkin lymphoma (B-NHL). B-NHL subtypes most frequently associated with HCV are marginal zone lymphoma and diffuse large B-cell lymphoma. The most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B-NHL regression after HCV eradication by antiviral therapy (AVT). In fact, for indolent HCV-associated B-NHL, first-line AVT instead of standard immune-chemotherapy might be considered. Full-Text PDF Open Access We read with interest the review by Peveling-Oberhag et al. [[1]Peveling-Oberhag J. Arcaini L. Hansmann M.L. Zeuzem S. Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management.J Hepatol. 2013; 59: 169-177Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar] that provides a very exhaustive picture of the knowledge about HCV-related B-cell non-Hodgkin lymphomas (NHL), from its connection with the mixed cryoglobulinemia (MC) condition and epidemiology to pathomechanisms, passing through therapeutic options. In spite of the multiple pathogenetic hypotheses proposed for HCV-related NHL [[2]Zignego A.L. Gragnani L. Giannini C. Laffi G. The hepatitis C virus infection as a systemic disease.Intern Emerg Med. 2012; 7: S201-S208Crossref PubMed Scopus (41) Google Scholar], since the link between malignancy and infection was shown [3Ferri C. La Civita L. Caracciolo F. Zignego A.L. Non-Hodgkin's lymphoma: possible role of hepatitis C virus.Jama. 1994; 272 ([letter]): 355-356Crossref PubMed Scopus (66) Google Scholar, 4Ferri C. Caracciolo F. Zignego A.L. La Civita L. Monti M. Longombardo G. et al.Hepatitis C virus infection in patients with non-Hodgkin's lymphoma.Br J Haematol. 1994; 88: 392-394Crossref PubMed Scopus (423) Google Scholar, 5Pozzato G. Mazzaro C. Crovatto M. Modolo M.L. Ceselli S. Mazzi G. et al.Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia.Blood. 1994; 84: 3047-3053PubMed Google Scholar], the authors clearly explained the research advances, summarizing them in three different theories: the sustained B cell stimulation, the direct oncogenic potential of viral proteins, and the genetic virus-induced damage by a so called "hit and run" action. Interestingly, the authors include microRNA dysregulation in the dissertation about the first theory, suggesting a key role of miR-26b downregulation in undermining tumor suppression [[6]Peveling-Oberhag J. Crisman G. Schmidt A. Doring C. Lucioni M. Arcaini L. et al.Dysregulation of global microRNA expression in splenic marginal zone lymphoma and influence of chronic hepatitis C virus infection.Leukemia. 2012; 26: 1654-1662Crossref PubMed Scopus (88) Google Scholar]. We could recently confirm these data on NHLs and also, consistently increase the potential importance of miR-26b levels in determining HCV-related lymphoproliferation [[7]Fognani E. Giannini C. Piluso A. Gragnani L. Monti M. Caini P. et al.Role of microRNA profile modifications in hepatitis C virus-related mixed cryoglobulinemia.PLoS One. 2013; 8: e62965Crossref PubMed Scopus (42) Google Scholar]. In fact, our results showed miR-26b downregulation not only in NHL, but also in MC patients, suggesting its involvement also in this condition, considered to be a prelymphomatous disorder. More interestingly, in patients who, after antiviral therapy, experienced viral eradication, the MC syndrome disappeared and miR-26b expression was restored to normal levels. From a translational point of view, we could show the usefulness of miR-26b detection in PBMCs, obtainable through non-invasive blood sampling; this was especially interesting in consideration of the difficulties in detecting miR-26b modifications in serum samples of the same MC or NHL patients (personal, unpublished data), making the PBMC test the easiest way to evaluate this potential marker through a simple blood drawn. The following, so far unexplored, step will therefore be the identification of miR-26b target genes; Peveling and colleagues already suggested the NEK6 gene coding for a kinase involved in the initiation of mitosis [[6]Peveling-Oberhag J. Crisman G. Schmidt A. Doring C. Lucioni M. Arcaini L. et al.Dysregulation of global microRNA expression in splenic marginal zone lymphoma and influence of chronic hepatitis C virus infection.Leukemia. 2012; 26: 1654-1662Crossref PubMed Scopus (88) Google Scholar]. In addition, we proposed the lymphoid enhancer factor 1 (LEF-1) gene [[7]Fognani E. Giannini C. Piluso A. Gragnani L. Monti M. Caini P. et al.Role of microRNA profile modifications in hepatitis C virus-related mixed cryoglobulinemia.PLoS One. 2013; 8: e62965Crossref PubMed Scopus (42) Google Scholar]. LEF-1 is a nuclear transcription factor transiently expressed in the pro-B and not detectable in mature B cells, but recently indicated as a specific target of miR-26b [[8]Zhang Z. Florez S. Gutierrez-Hartmann A. Martin J.F. Amendt B.A. MicroRNAs regulate pituitary development, and microRNA 26b specifically targets lymphoid enhancer factor 1 (Lef-1), which modulates pituitary transcription factor 1 (Pit-1) expression.J Biol Chem. 2010; 285: 34718-34728Crossref PubMed Scopus (78) Google Scholar]; previous studies showed elevated levels of LEF-1 in human cancers, in chronic lymphatic leukemia [[9]Gutierrez Jr., A. Tschumper R.C. Wu X. Shanafelt T.D. Eckel-Passow J. Huddleston 3rd, P.M. et al.LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis.Blood. 2010; 116: 2975-2983Crossref PubMed Scopus (122) Google Scholar] and in a wide cohort of diffuse large B cells lymphomas [[10]Cubedo E. Gentles A.J. Huang C. Natkunam Y. Bhatt S. Lu X. et al.Identification of LMO2 transcriptome and interactome in diffuse large B-cell lymphoma.Blood. 2012; 119: 5478-5491Crossref PubMed Scopus (35) Google Scholar], making this a potential target of special interest in the pathogenetic research field. In conclusion, our results on HCV positive MC strengthen previous data on the importance of miR-26b modulation in HCV-related NHL, opening new perspectives for further studies on target genes and also aimed to a better definition of this microRNA as disease biomarker. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.