Inflammatory microRNAs in liver cancer

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Chronic inflammation is one of the hallmarks of cancer. Hepatocellular carcinoma (HCC), responsible for > 0.5 million deaths worldwide per annum, is closely related to chronic inflammation, commonly caused by hepatitis B or C virus infections or steatohepatitis. Interleukin-6, an inflammatory cytokine, which signals via Jak/STAT3, often shows increased activity in HCC. In addition, expression levels of certain miRNAs (small non-coding RNAs, which negatively regulate gene expression) are also altered in HCC and other cancers. Here, we aim to investigate the role of miRNAs in the regulation of IL-6/Jak/STAT3 signalling in hepatoma cells and non-transformed hepatocytes. We will not only study intracellular miRNAs, but will pay special attention to secreted miRNAs, isolated from blood samples. Potential targets of selected miRNAs shall be identified by detailed analysis and validation of corresponding mRNA expression data. In an independent approach, we will study miRNAs targeting key players of the IL-6 signal transduction cascade (e.g. STAT3, SOCS3). Results obtained with cell lines will be translated to samples from HCC patients (blood, tumour tissue, surrounding liver tissue) and to primary hepatocytes isolated from these patients. The project will increase our knowledge on the relevance of intracellular and secreted miRNAs in inflammatory signal transduction. We expect moreover that our approach will lead to the identification of (a) miRNAs, which could be targeted therapeutically to modulate IL-6/STAT3 signal transduction and (b) miRNAs, which may be eventually used as biomarkers in the diagnosis and prognosis of HCC. This would be most useful in the surveillance of risk patients with chronic hepatitis or liver cirrhosis to better predict potential progression into HCC at an early stage when treatment success rates are still favourable.