Pharmacologic IL-6Rα inhibition in cholangiocarcinoma promotes cancer cell growth and survival.
Aged
Antibodies, Monoclonal, Humanized
/ pharmacology
Apoptosis
/ drug effects
Bile Duct Neoplasms
/ metabolism
Cell Line, Tumor
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Cholangiocarcinoma
/ metabolism
Down-Regulation
/ drug effects
Female
G2 Phase
/ drug effects
Gallbladder
/ metabolism
Humans
Interleukin-6
/ metabolism
Male
Middle Aged
Mitosis
/ drug effects
Models, Biological
Phosphorylation
/ drug effects
Phosphotyrosine
/ metabolism
Receptors, Interleukin-6
/ antagonists & inhibitors
Recombinant Fusion Proteins
/ pharmacology
STAT3 Transcription Factor
/ metabolism
Signal Transduction
/ drug effects
Survival Analysis
Cholangiocarcinoma
Gallbladder cancer
IL-6 receptor signaling
IL-6 trans-signaling
STAT3
Journal
Biochimica et biophysica acta. Molecular basis of disease
ISSN: 1879-260X
Titre abrégé: Biochim Biophys Acta Mol Basis Dis
Pays: Netherlands
ID NLM: 101731730
Informations de publication
Date de publication:
01 02 2019
01 02 2019
Historique:
received:
21
06
2018
revised:
25
10
2018
accepted:
07
11
2018
pubmed:
13
11
2018
medline:
19
9
2019
entrez:
13
11
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30419338
pii: S0925-4439(18)30451-4
doi: 10.1016/j.bbadis.2018.11.006
pii:
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Interleukin-6
0
Receptors, Interleukin-6
0
Recombinant Fusion Proteins
0
STAT3 Transcription Factor
0
Phosphotyrosine
21820-51-9
tocilizumab
I031V2H011
olamkicept
ZW1H7GZO9W
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
308-321Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.