Abstract 3003: Immune cell-related microRNA-155 is associated with human liver cirrhosis and hepatocellular carcinoma

Abstract

Abstract Liver cirrhosis, a major hepatocellular carcinoma (HCC) risk factor, is caused by chronic liver disease (CLD) of various etiologies with ambiguous underlying mechanisms. Gene profiling has illustrated that CLD etiologies differ and are associated with cytokine up-regulation. Recently, microRNAs (miRNAs), noncoding-RNA gene regulators, have been utilized as effective molecular biomarkers in many cancer types, including HCC. We investigated whether unique miRNAs are associated with CLD and HCC. We examined miRNA array profiles of 58 human liver tissue specimens with end-stage CLD (hepatitis B virus, hepatitis C virus, Wilson's disease, autoimmune hepatitis, alcoholic liver disease and primary biliary cirrhosis) and a normal liver pool. We compared the differentially expressed miRNAs between CLDs and normal liver, among CLDs and between etiologically equivalent CLD and HCC. Significant differentially expressed CLD-miRNAs were validated by quantitative-real time PCR (qRT-PCR). MiRNA and immune cell expression was measured in CLD, HCC or human peripheral blood mononuclear cells (PBMC) by qRT-PCR or immunohistochemistry. Correlation analysis between etiology-specific miRNAs and mRNAs were performed, followed by pathway analysis of the correlating mRNAs. Statistical class comparison analyses revealed that unique miRNAs were associated with each CLD group and among CLD etiologies, with only one miRNA commonly altered among CLDs (p=0.05; 10 fold cross-validation; 10k permutation). miRNA expression correlated well between array and qRT-PCR analyses (spearman r= 0.53-0.83, p= 0.03-0.001). We also found that many CLD-miRNA alterations were maintained in HCC. In particular, immune-related miR-155 was significantly up-regulated in CLDs, HCC, nontumor tissue, metastasis tissue specimens and PBMC treated with pro-metastatic colony stimulating factor 1 (CSF1) or osteopontin (OPN). MiR-155 was associated with T regulatory cells (Treg) and both were elevated by pro-inflammatory cytokines. Moreover, high miR-155 expression in nontumor tissues was associated with poor overall HCC patient survival (p=0.0244). Correlation analysis revealed that miR-155 was associated with distinct gene expression pathways in each CLD etiology. In sum, CLD miRNAs are mainly etiologically distinct and are coupled to immune responses and tumorigenesis. Our work suggests that miR-155 may modulate Tregs and hence, functionally contribute to CLD and HCC progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3003.