During HCV DAA Therapy Plasma Mip1B, IP10, and miRNA Profile Are Distinctly Associated with Subsequent Diagnosis of Hepatocellular Carcinoma: A Pilot Study

SIMPLE SUMMARY: Hepatitis C virus (HCV) therapy lowers risk of liver cancer. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate immune response and pathogenesis of disease. We evaluated soluble markers of interferon signaling and liver cirrhosis, plasma miRNAs and other non-coding RNAs throughout HCV therapy prior to diagnosis of liver cancer to understand factors involved in the early stages of the cancer pathogenesis. Our results of the absence of cancer pathway suppressive miRNAs, in combination with serum immune biomarkers, may help enhance ability to identify patients at high risk for liver cancer and provide timely treatments. ABSTRACT: Background: Hepatitis C virus (HCV) therapy lowers risk of hepatocellular carcinoma (HCC). Little is known about factors driving/preceding HCC in treated persons. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate host response and pathogenesis of disease. We investigated plasma levels of these RNAs and select serum markers before, during, and after HCV therapy, preceding HCC. Methods: Of 187 DAA treated HCV patients where therapy oriented longitudinal sampling was performed at a time without HCC diagnosis, 9 were subsequently diagnosed with HCC within 2 years of therapy. They were matched with 7 patients not diagnosed with HCC over the same time period. RNASeq was performed on plasma, and serum was assessed for biomarkers of inflammation by ELISA. Results: HCC diagnosis was 19 months (6–28) after therapy start in the HCC group. 73 and 63 miRs were differentially expressed at baseline (before DAA therapy) and 12 weeks after DAA therapy comparing HCC and non-HCC groups. Several lncRNA- showed differential expression as well. Several miRNA suppressors of cancer-related pathways, lncRNA- and mRNA-derived stabilized short RNAs were consistently absent in the plasma of patients who developed HCC. Serum IP10, and MCP-1 level was higher in the HCC group 12 weeks after therapy, and distinct miRNAs correlated with IP10 and MCP-1. Finally, in a focused analysis of 8 miRNAs best associated with HCC we observed expression of mi576 and mi-5189 correlation with expression of a select group of PBMC mRNA. Conclusions: These results are consistent with complex interplay between RNA-mediated host immune regulation and cancer suppression, strikingly skewed 12 weeks following therapy, prior to HCC diagnosis.