Journal
ONCOTARGET
Volume 7, Issue 52, Pages 86766-86780Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.13575
Keywords
trabectedin; Intrahepatic cholangiocarcinoma; microarray; microRNA; silencing
Categories
Funding
- Associazione Italiana Ricerca sul Cancro-AIRC 5X1000, Ministry of Health
- Fondazione Piemontese per la Ricerca sul Cancro - Onlus - Identification of new druggable pathways in intrahepatic cholangiocarcinoma 5 per Mille Ministero della Salute
- Universita di Torino anno - Fondo per la ricerca locale (Linea B) project title: Transcriptomic and genetic analysis of paired primary and recurrent intrahepatic cholangiocarcinoma [LEOF_RIC_LOC_14_01]
- University of Turin
- FPO [16:30]
- Compagnia di San Paolo
- Lauretana
- Identificazione di nuove vie di trasduzione del segnale intracellulare sensibili ai farmaci nel colangiocarcinoma intraepatico (ICC) [16:30]
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Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy with limited therapeutic options. Trabectedin has a high antitumor activity in preclinical models of biliary tract carcinoma (BTC), being a promising alternative treatment. Here, we studied the effect of trabectedin at transcriptomic level on an ICC patient derived xenograft (PDX) and on the derived cell line, MT-CHC01. Further, putative targets of trabectedin were explored in the in vitro model. In vitro, trabectedin inhibited genes involved in protein modification, neurogenesis, migration, and motility; it induced the expression of genes involved in keratinization, tissues development, and apoptotic processes. In the PDX model, trabectedin affected ECM-receptor interaction, focal adhesion, complement and coagulation cascades, Hedgehog, MAPK, EGFR signaling via PIP3 pathway, and apoptosis. Among down-regulated genes, we selected SYK and LGALS1; their silencing caused a significantly reduction of migration, but did not affect proliferation in in vitro models. In MT-CHC01 cells, 24 microRNAs were deregulated upon drug treatment, while only 5 microRNAs were perturbed by trabectedin in PDX. The target prediction analysis showed that SYK and LGALS1 are putative targets of up-regulated microRNAs. In conclusion, we described that trabectedin affected genes and microRNAs involved in tumor progression and metastatic processes, reflecting data previously obtained at macroscopically level; in particular, we identified SYK and LGALS1 as new putative targets of trabectedin.
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