Inflammatory miRNAs in liver cancer (HepmiRSTAT)

Hepatocellular carcinoma (HCC), is closely related to chronic inflammation, and interleukin-6, an inflammatory cytokine often shows increased activity in HCC. We will investigate the role of miRNAs in the regulation of IL-6/Jak/STAT3 signalling in hepatoma cells and non-transformed hepatocytes.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. These approaches 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. The project is funded as an Inter project by the FNR and the DFG and involves the collaboration with Prof. Frank Lammert, Clinic for Internal Medicine, Saarland University Medical School in Homburg (start 2013).

miRNA Projects

• Melanomics: Advancing our understanding of melanoma biology by integrating data from melanoma genomes, transcriptome and miRNomes
• Dynamic change of host gastrointestinal microbiome and immune status in relation to mucosal barrier effects during chemotherapy and immune ablative intervention in humans
• Analysis of secreted miRNAs in blood samples from healthy donors and melanoma patients: mechanisms of secretion of miRNAs and potential function as internal messengers
• Role of miRNAs in drug-resistance of advanced melanoma and identification of novel kinase inhibitors to overcome drug-resistance of advanced melanoma
• Role of individual miRNAs in development and maintenance of melanoma and other cancers
• Dynamic expression changes of miRNomes and mRNomes

Effects of inflammatory cytokines and hypoxia on cancermetabolism in a systems approach

This project focusses on IL6-type cytokine and hypoxia crosstalk in hepatocellular carcinoma. IL6 is a crucial factor implicated in tumor-promoting inflammation in hepatocellular carcinoma.IL6-type cytokine signaling effects are mediated by multiple pathways including STAT3, the Mek/Erk-, the PI3K/Akt-pathway and hypoxia inducible factor (HIF) 1a. HIF1a is the “master” regulator of cellular responses to low oxygen levels (hypoxia) and is known to influence metabolic pathways implicated in cancer. Since IL6-type cytokines and hypoxia are crucially involved in cancer and regulate metabolism, we aim to investigate their combined effects in liver cells. Combining transcriptomics microarray data with metabolomics measurements and intracellular metabolic conversion rates, we propose to elucidate disease-related effects of cytokines and reduced oxygen levels in a systems level approach. The integrated analysis of the obtained data will reveal effects on cellular metabolism caused by changes in the transcriptional network of the cell, thus providing information on potential therapeutic targets. Funded as UL tandem project (C. Haan, K. Hiller, Metabolomics Research Group, LCSB, Start: 2012).

Molecular mechanism underlying the hyperactivity of disease-relevant Jak2 mutants and their targeting by inhibitors

Recently mutations in Jak2 (V617F and others) were found with high incidence in patients with myeloproliferative neoplasms.Since then many activating mutations in Jaks have been described in various disease settings. These hyperactive mutants lead to deregulated signaling and to the hyperproliferation of several cell lineages. For the development of novel therapeutic approaches it is essential to understand signaling through constitutively active Jak mutants. In collaboration with Prof. Fred Schaper (Systems Biology Department, Otto von Guericke University, Magdeburg, Germany) we investigate the molecular link between Erk1/2 and PI3K/Akt pathways in signaling through constitutively active Jak2V617F. The effect of ATP competitive small molecule inhibition of constitutively active Jaks is investigated in collaboration with Dr. Guy Berchem (CHL, Luxembourg). (UL-project MyeloJak, I. Behrmann/C. Haan, 2010-2013).

Contributions of the different Janus kinases to cytokine signaling

The different Janus kinases can have differently important roles in promoting signal transduction. Many pharmaceutical companies seek small molecule Janus kinase inhibitors for treatment of inflammation and malignancies.Thus, it is important to know which Jak has to be targeted to achieve inhibition of signaling. We explore the roles of different Jaks using using engineered cells initially lacking one specific Jak, in which either wild-type, kinase-inactive or “analogue-sensitive” Jak mutants are reconstituted. In collaboration with Novartis Institute of Biomedical Research (NIBR) we have recently shown that Jak1 has a dominant role over Jak3 in signal transduction through gc-containing cytokine receptors. Specific Jak3 inhibition was insufficient to block signaling and these data challenge the notion that selective ATP-competitive Jak3 kinase inhibitors will be effective in immunosuppression. Currently we are investigating the involvement of individual Jaks in interferon (IFN)-g and  IL27 signal transduction (collaboration with Dr. Heike M. Hermanns, Würzburg, Germany).