HCV-related lymphatic and hepatic malignancies are associated with different microRNA expression patterns in PBMCs

HCV infection leads to chronic liver damage often evolving to Hepatocellular Carcinoma (HCC), but also promotes lymphoproliferative disorders (LPDs) such as mixed cryoglobulinemia (MC) and Non Hodgkin Lymphomas (NHL). Modified expression levels of specific microRNAs have been associated with different autoimmune/lymphoproliferative or neoplastic disorders. We previously showed a downregulation of miR-26b in HCV-related MC and NHL. In this study we analyzed the expression of a panel of microRNAs in peripheral blood mononuclear cells (PBMCs) from a large population of HCV patients with or without LPDs or HCC, in order to identify non-invasive markers of such evolutions of HCV infection. PBMCs levels of miR-Let7d, miR-16, miR-21, miR-26b, miR-146a and miR-155 were evaluated by Real Time PCR in 187 HCV patients (75 with MC [HCV-MC], 11 with HCV-related NHL [HCV-NHL], 20 with HCV-related HCC [HCV-HCC], 81 without LPD or HCC [HCV]) and in 35 healthy blood donors (HS). A significant increase of miR-21 (p< 0.001) expression was detected in PBMCs from only NHL patients, while miR-155 and miR-16 were upregulated both in NHL (p< 0.05) and HCC subjects (p<0.001), when compared to the other groups. A similar level for miR-146a was observed in all groups, except for the HCV-HCC patients, where miR-146a resulted upregulated (p<0.001). A significant decrease of miR-26b was observed in both MC and NHL subjects (p<0.05) when compared to HS and HCV groups. The upregulation of miR-16 and miR-155 is consistent with their reported role as “oncogenic microRNAs” in both HCC and lymphomas, while the upregulation of miR-21 only in the HCV-NHL group confirms its specific role in hematological malignancy. Interestingly, the downregulation of miR-26b in HCV-related LPDs, but not in HCC, suggests its pathogenetic relevance and its potential use as biomarker for evolution into LPDs. Furthermore, the upregulation of miR-146a in PBMC was shown as peculiar profile of HCC patients, suggesting that this could identify an evolution to a hepatic malignancy. In conclusion, this study shows that microRNAs are differently modulated in PBMCs from HCV patients who developed LPDs, NHL or HCC and thus, they could represent clinically relevant tools, useful to discriminate between the two major HCV-related malignancies.