Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Kleinegger, F.
Investigations on IL-6Rα and IL-6 mediated signaling in cholangiocarcinoma
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medical University of Graz; 2019. pp. 102
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- Autor*innen der Med Uni Graz:
- Kleinegger Florian
- Betreuer*innen:
- Fickert Peter
- Haybäck Johannes
- Rinner Beate
- Altmetrics:
- Abstract:
- Biliary tract cancer (BTC) is the second most frequent primary liver cancer. Due to high mortality rates and missing therapy options, constant research is necessary to provide insights into BTC pathogenesis. BTCs are classified based on their anatomical location in intrahepatic cholangiocarcinoma (iCCA), extrahepatic CCA (eCCA) and gallbladder cancer (GBC), whereas the latter is the most common form worldwide. Chronic inflammation is one of the most leading causes for BTC. The cytokine interleukin 6 (IL-6) is one of the major mediators for inflammatory signals. IL-6 transduces signals via the IL-6 receptor (IL 6Rα). This receptor can occur either in membrane-bound (mIL-6R) form or in soluble form (sIL 6R). The presence of a sIL-6R form enables IL-6 to influence cells lacking IL-6Rα expression. This IL-6 signaling process was termed IL-6 trans-signaling, whereas signal transduction mediated by mIL-6R is termed IL-6 classic signaling. The present study was based on the hypotheses that IL-6Rα has a pivotal role in the carcinogenesis of BTC and that IL-6 classic signaling and IL-6 trans-signaling influence CCA cells differently, hence the form of IL-6 signaling plays a role for CCA cells. To test these hypotheses, GBC tissues were analyzed regarding IL-6Rα expression as tissue microarray and fresh frozen tissues. Non-neoplastic, not inflamed gallbladders served as controls. The results of this study showed a significantly reduced expression of IL-6Rα in GBC on protein and RNA level. Moreover, a significant association between high IL-6Rα expression and better overall survival of GBC patients was found. In vitro experiments on different CCA cell lines showed that activation of IL-6 trans-signaling plays a rather minor role in the cellular processes observed in CCA. In contrast, activation of IL-6 classic signaling induced increased cell proliferation and reduced apoptosis. Similar results were achieved by specific inhibition of IL-6 trans-signaling. These observations indicate a superior role of both, activation of IL-6 classic signaling and inhibition of IL-6 trans-signaling. In conclusion, this study describes an association between IL-6Rα and BTC, suggesting an important role of IL-6Rα in cholangiocarcinogenesis. Furthermore, differentiation between IL-6 classic signaling and IL-6 trans-signaling brought more information about the different forms of IL-6 signal transduction in CCA. Therefore, the data obtained in this study make an important contribution to the understanding of BTC and might be used for the development of new therapeutic strategies in the near future.