MicroRNAs associated with the efficacy of photodynamic therapy in biliary tract cancer cell lines.
Photodynamic therapy (PDT) is a palliative treatment option for unresectable hilar biliary tract cancer (BTC) showing a considerable benefit for survival and quality of life with few side effects. Currently, factors determining the cellular response of BTC cells towards PDT are unknown. Due to their multifaceted nature, microRNAs (miRs) are a promising analyte to investigate the cellular mechanisms following PDT. For two photosensitizers, Photofrin® and Foscan®, the phototoxicity was investigated in eight BTC cell lines. Each cell line (untreated) was profiled for expression of n=754 miRs using TaqMan® Array Human MicroRNA Cards. Statistical analysis and bioinformatic tools were used to identify miRs associated with PDT efficiency and their putative targets, respectively. Twenty miRs correlated significantly with either high or low PDT efficiency. PDT was particularly effective in cells with high levels of clustered miRs 25-93*-106b and (in case of miR-106b) a phenotype characterized by high expression of the mesenchymal marker vimentin and high proliferation (cyclinD1 and Ki67 expression). Insensitivity towards PDT was associated with high miR-200 family expression and (for miR-cluster 200a/b-429) expression of differentiation markers Ck19 and Ck8/18. Predicted and validated downstream targets indicate plausible involvement of miRs 20a*, 25, 93*, 130a, 141, 200a, 200c and 203 in response mechanisms to PDT, suggesting that targeting these miRs could improve susceptibility to PDT in insensitive cell lines. Taken together, the miRNome pattern may provide a novel tool for predicting the efficiency of PDT and-following appropriate functional verification-may subsequently allow for optimization of the PDT protocol.
Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Muellner Hauptstrasse 48, Salzburg 5020, Austria. and.wagner@salk.at.
Andrej
A
Wagner
Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Muellner Hauptstrasse 48, Salzburg 5020, Austria. ch.mayr@salk.at.
Christian
C
Mayr
Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Muellner Hauptstrasse 48, Salzburg 5020, Austria. doris.bach@gmx.at.
Doris
D
Bach
Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg 5020, Austria. r.illig@salk.at.
Romana
R
Illig
Laboratory of Photodynamic Inactivation of Microorganisms, Department of Materials Science and Physics, University of Salzburg, Salzburg 5020, Austria. kristjan.plaetzer@sbg.ac.at.
Kristjan
K
Plaetzer
Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Muellner Hauptstrasse 48, Salzburg 5020, Austria. f.berr@salk.at.
Frieder
F
Berr
Division of Oncology, Medical University Graz, Graz 8036, Austria. martin.pichler@medunigraz.at.
Martin
M
Pichler
Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg 5020, Austria. d.neureiter@salk.at.
Daniel
D
Neureiter
Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Muellner Hauptstrasse 48, Salzburg 5020, Austria. t.kiesslich@salk.at.
Tobias
T
Kiesslich
D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019295:Computational Biology; D003198:Computer Simulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D063990:Gene Ontology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008652:Mesoporphyrins / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010778:Photochemotherapy; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D008652:Mesoporphyrins; D035683:MicroRNAs; C072269:temoporfin; D005978:Glutathione