title: Gene and microRNA modulation upon trabectedin treatment in a human intrahepatic cholangiocarcinoma paired patient derived xenograft and cell line.
abstract: 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.
authors.affiliation: University of Turin Medical School, Department of Oncology, IRCCS-Institute Candiolo, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Peraldo Neia
authors.affiliation: Medical Oncology Division, Fondazione del Piemonte per l'Oncologia (FPO), IRCCS-Institute Candiolo, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cavalloni
authors.affiliation: Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
authors.affiliation: Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ostano
authors.affiliation: University of Turin Medical School, Department of Oncology, IRCCS-Institute Candiolo, Italy.|Medical Oncology Division, Fondazione del Piemonte per l'Oncologia (FPO), IRCCS-Institute Candiolo, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
authors.affiliation: University of Turin Medical School, Department of Oncology, IRCCS-Institute Candiolo, Italy.|Medical Oncology Division, Fondazione del Piemonte per l'Oncologia (FPO), IRCCS-Institute Candiolo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Leone
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics; D016000:Cluster Analysis; D004149:Dioxoles / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D063990:Gene Ontology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D059467:Transcriptome / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D035683:MicroRNAs; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
keywords: Intrahepatic cholangiocarcinoma; microRNA; microarray; silencing; trabectedin