Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Kleinegger, F; Hofer, E; Wodlej, C; Golob-Schwarzl, N; Birkl-Toeglhofer, AM; Stallinger, A; Petzold, J; Orlova, A; Krassnig, S; Reihs, R; Niedrist, T; Mangge, H; Park, YN; Thalhammer, M; Aigelsreiter, A; Lax, S; Garbers, C; Fickert, P; Rose-John, S; Moriggl, R; Rinner, B; Haybaeck, J.
Pharmacologic IL-6Rα inhibition in cholangiocarcinoma promotes cancer cell growth and survival.
Biochim Biophys Acta Mol Basis Dis. 2019; 1865(2):308-321
Doi: 10.1016/j.bbadis.2018.11.006
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- Führende Autor*innen der Med Uni Graz
- Haybäck Johannes
- Kleinegger Florian
- Co-Autor*innen der Med Uni Graz
- Aigelsreiter Ariane
- Birkl-Töglhofer Anna Maria
- Fickert Peter
- Golob-Schwarzl Nicole
- Kraßnig Stefanie
- Mangge Harald
- Niedrist Tobias Josef
- Reihs Robert
- Rinner Beate
- Skofler Christina
- Stallinger Alexander
- Thalhammer Michael
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- Abstract:
- Biliary tract cancer (BTC) represents a malignant tumor of the biliary tract including cholangiocarcinoma (CCA) and the carcinoma of the gallbladder (GBC) with a 5-year survival rate between 5 and 18% due to late diagnosis and rapid disease progression. Chronic inflammation is one of the main risk factors for CCA and GBC in particular. IL-6, as a mediator of inflammation, can act through a membrane-bound receptor alpha-chain (mIL-6R, "IL-6 classic signaling") or via soluble forms (sIL-6R, "IL-6 trans-signaling"). However, little is known about the impact on cellular responses of IL-6 trans-signaling on BTC. We analyzed primary tumors as whole sections and as tissue microarrays, and also searched The Cancer Genome Atlas database. Compared to non-neoplastic, non-inflamed gallbladder tissue, IL-6Rα was downregulated in GBC, and this correlated with the patients' overall survival. Furthermore, different CCA cell lines and compounds for activation (IL-6 and Hyper-IL-6) or inhibition (Tocilizumab and sgp130Fc) of IL-6 classic signaling and trans-signaling were used to determine their effects on cellular processes between the two modes of IL-6 signaling. Inhibition of IL-6 trans-signaling by sgp130Fc reduced CCA cell line viability and apoptosis, whereas migration and proliferation were increased. We conclude that IL-6Rα expression is a good prognostic marker for GBC, and that the blocking of IL-6 trans-signaling and activation of IL-6 classic signaling have tumor promoting activity. These findings warrant the exclusion of patients with GBC or other malignancies associated with bile metabolism from IL-6R inhibitor therapy. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
- Find related publications in this database (Keywords)
- IL-6 receptor signaling
- IL-6 trans-signaling
- Cholangiocarcinoma
- Gallbladder cancer
- STAT3