Profiling of gallbladder carcinoma reveals distinct miRNA profiles and activation of STAT1 by the tumor suppressive miRNA-145-5p

Goeppert B, Truckenmueller F, Ori A, Fritz V, Albrecht T, Fraas A, Scherer D, Silos RG, Sticht C, Gretz N, Mehrabi A, Bewerunge-Hudler M, Pusch S, Bermejo JL, Dietrich P, Schirmacher P, Renner M, Roessler S (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Scientific Reports Nature Publishing Group: Open Access Journals - Option B

Book Volume: 9

DOI: 10.1038/s41598-019-40857-3

Abstract

Gallbladder carcinoma (GBC) is a biliary tract cancer with few treatment options and poor prognosis. Radical surgery is the only potentially curative treatment option but most patients diagnosed with GBC are unresectable. Thus, there is a great need for the development of new treatment options including targeted therapy. Here, we aimed at identifying deregulated miRNAs and affected pathways involved in GBC development and progression. We performed global miRNA profiling of 40 GBC and 8 normal gallbladder tissues and identified large differences with 30% of miRNAs being differentially expressed (false discovery rate: FDR < 0.001). We found 24 miRNAs to be differentially regulated in GBC with poor outcome (p < 0.05) of which miR-145-5p was the most downregulated miRNA. Overexpression of miR-145-5p significantly reduced cell proliferation and colony formation. Gene expression analysis of cells expressing miR-145-5p mimics revealed activation of the Signal transducer and activator of transcription 1 (STAT1) signaling pathway which is mainly tumor suppressive. Furthermore, the activation of STAT1 by miR-145-5p was specifically observed in gallbladder carcinoma and cholangiocarcinoma but not in hepatocellular carcinoma cells. The Protein Tyrosine Phosphatase Receptor Type F (PTPRF) is downregulated upon miR-145 expression and may be involved in STAT1 regulation. In addition, we found that the STAT1-regulated protein IRF7 is downregulated in GBC compared to normal gallbladder tissue and low IRF7 expression is associated with significantly lower overall survival of GBC patients. Thus, this study identified GBC patient subgroups and provides new mechanistic insights in the tumor suppressive function of miR-145-5p leading to activation of STAT1 signaling.

Authors with CRIS profile

Valerie Fritz Lehrstuhl für Biochemie und Molekulare Medizin Peter Dietrich Lehrstuhl für Biochemie und Molekulare Medizin

Involved external institutions

Universitätsklinikum Heidelberg DE Germany (DE) Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut (FLI) DE Germany (DE) Universitätsklinikum Mannheim DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE)

How to cite

APA:

Goeppert, B., Truckenmueller, F., Ori, A., Fritz, V., Albrecht, T., Fraas, A.,... Roessler, S. (2019). Profiling of gallbladder carcinoma reveals distinct miRNA profiles and activation of STAT1 by the tumor suppressive miRNA-145-5p. Scientific Reports, 9. https://dx.doi.org/10.1038/s41598-019-40857-3

MLA:

Goeppert, Benjamin, et al. "Profiling of gallbladder carcinoma reveals distinct miRNA profiles and activation of STAT1 by the tumor suppressive miRNA-145-5p." Scientific Reports 9 (2019).

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