Gene and microRNA modulation upon trabectedin treatment in a human intrahepatic cholangiocarcinoma paired patient derived xenograft and cell line
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Caterina Peraldo Neia1, Giuliana Cavalloni2, Giovanna Chiorino3, Paola Ostano3, Massimo Aglietta1,2, Francesco Leone1,2
1University of Turin Medical School, Department of Oncology, IRCCS-Institute Candiolo, Italy
2Medical Oncology Division, Fondazione del Piemonte per l’Oncologia (FPO), IRCCS-Institute Candiolo, Italy
3Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy
Caterina Peraldo Neia, email: [email protected]
Keywords: trabectedin, Intrahepatic cholangiocarcinoma, microarray, microRNA, silencing
Received: March 25, 2016 Accepted: November 09, 2016 Published: November 24, 2016
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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