Inflammatorische microRNAs bei Leberkrebs

• Antragsteller: Professor Dr. Frank Lammert
• Fachliche Zuordnung: Hämatologie, Onkologie ; Biochemie ; Gastroenterologie
• Förderung: Förderung von 2013 bis 2018
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 230854839

• Erstellungsjahr: 2017

Zusammenfassung der Projektergebnisse

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 noncoding 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 nontransformed 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.

Projektbezogene Publikationen (Auswahl)

• IL-27 elicits responses similar to Interferon-gamma in non-hematopoietic cells. Cytokine vol. 76, p. 101, ISSN 10434666
  Rolvering, C., A. Zimmer, I. Behrmann, C. Haan
  
• MicroRNAs as modulators of cytokine responses in cancer. 2015 Aegean Conferences Series vol. 88, p. 25
  Behrmann, I., S. Reinsbach, M. Schmitt, P. Nazarov, D. Philippidou, F. Servais, M. Hamdorf, L. Vallar, C. Margue, S. Kreis
  
• Role of microRNAs in signal transduction pathways of the inflammatory cytokine Interleukin-6: relevance for liver diseases. Cytokine vol. 76, p. 99, ISSN 10434666
  Servais, F.A., M. Kirchmeyer, M. Hamsdorf, C. Haan, M. Casper, F. Lammert, P. Nazarov, L. Vallar, S. Kreis, and I. Behrmann
  
• Cytokines and hepatocellular carcinoma: potential progression markers and cell type-specific modulators of the miRNome (e.g. interleukin-6 and other Jak/STAT activating cytokines). 2016 Cytokine vol. 87, p. 71-72, ISSN 1043-4666
  Kirchmeyer, M., F. A. Servais, M. Hamdorf, C. Haan, P. Nazarov, L. Vallar, M. Casper, M. Glanemann, A. Arslanow, C. Rubie, F. Lammert, S. Kreis, I. Behrmann
  
• Cytokines and hepatocellular carcinoma: potential progression markers and cell type-specific modulators of the miRNome (e.g. interleukin-6 and other Jak/STAT activating cytokines). 2016 Z. Gastroenterol. vol. 54(12), p. 1343-1404
  Kirchmeyer, M., F. A. Servais, M. Hamdorf, C. Haan, P. Nazarov, L. Vallar, M. Casper, M. Glanemann, A. Arslanow, C. Rubie, F. Lammert, S. Kreis, I. Behrmann
  
• Evaluation der pro-steatotischen Genvariante rs641738 im MBOAT7-Gen bei Patienten mit hepatozellulärem Karzinom (HCC). 2016 Z. Gastroenterol. vol. 54(12), p. 1343-1404
  Casper, M., M. Krawczyk, I. Behrmann, M. Glanemann, and F. Lammert
  
• Role of microRNAs in signal transduction of the inflammatory cytokine interleukin-6 in hepatocellular carcinoma cell lines and primary hepatocytes. 2016 European Journal of Cancer vol. 61, suppl. 1, p. 178, ISSN 0959-8049
  Servais, F., M. Kirchmeyer, M. Casper, M. Hamdorf, C. Haan, P. Nazarov, L. Vallar, C. Rubie, M. Glanemann, F. Lammert, S. Kreis, I. Behrmann
  
• Variant PNPLA3 increases the HCC risk: prospective study in patients treated at the Saarland University Medical Center. Zeitschr. Gastroenterol. 2016 54:585-586
  Casper, M., M. Krawczyk, I. Behrmann, M. Glanemann, and F. Lammert
  
• Crosstalk between different family members: IL27 recapitulates IFNy responses in HCC cells, but is inhibited by IL6-type cytokines. BBA Mol Cell Res. 2017 1864:516-526
  Rolvering, C., A. D. Zimmer, I. Kozar, H. M. Hermanns, E. Letellier, L. Vallar, P. V. Nazarov, N. Nicot, A. Ginolhac, S. Haan, I. Behrmann, and C. Haan