DOWNREGULATION OF PTEN AND IRS1 BY HCV 3A CORE PROTEIN TRIGGERS STEATOSIS IN HEPATOCYTES

marginal zone lymphoma (SMZL) is one of the few lymphoma sub entities consistently found associated with HCV infection.Micro-RNAs (miRNAs), small non-coding RNAs regulating gene expression, exhibit an oncogenic potential in various tumours and moreover, their expression has been shown to be influenced by chronic HCV infection.We investigated the influence of HCV infection on tumour miRNA expression in primary SMZL tissue.Methods: We performed a large-scale miRNA expression profiling analysis of 381 miRNAs by quantitative reverse-transcription PCR (Q-RT-PCR) on 26 microdissected splenic tissue samples, including 7 HCV positive and 8 HCV negative patients with SMZL as well as 11 non-tumorous controls.Results were validated by single assay Q-RT-PCR and on an independent set of 15 SMZL cases by miRNA in situ hybridisation.Results: Unsupervised hierarchical clustering of miRNA expression profiles demonstrated a distinct signature of SMZL compared to the healthy splenic marginal zone.A supervised analysis comparing tumorous vs. non-tumorous tissue revealed differentially expressed miRNAs, including ones previously recognized for their tumour suppressive or oncogenic potential.Five miRNAs were found significantly overexpressed in SMZL, including miR-21, miR-155, and miR-146a (p-values: 0.004, 0.002, 0.0002, respectively), while six miRNAs showed significantly lower expression, including miR-139, miR-345, miR-125a, and miR-126 (p-values: 0.0002, 0.007, 0.0006, 0.000003, respectively).We identified miR-26b, a miRNA with known tumour suppressive properties, as significantly down-regulated in SMZL arising in HCV positive patients (p-value: 0.0016).Conclusions: For the first time, we could identify miRNAs differentially expressed in SMZL by a global miRNA expression profiling, with possible implication in the pathogenesis of this lymphoma entity.Moreover, we found a designated tumour suppressor, miR-26b, with reduced expression in HCV positive SMZL-patients pointing to a possible oncogenic mechanism of HCV in lymphomagenesis.