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.
Highlights
Intrahepatic cholangiocarcinoma (ICC) is the second most common liver cancer type [1, 2]
We have recently demonstrated that trabectedin has an antitumor activity both in vitro and in vivo in preclinical models of human biliary tract carcinoma (BTC)
BTC is an aggressive neoplasia with a complex molecular pathogenesis; the current clinical approaches are limited and the poor prognosis, due to the scarce therapeutic options, encourages the evaluation of new drugs
Summary
Intrahepatic cholangiocarcinoma (ICC) is the second most common liver cancer type [1, 2] It is aggressive and with poor prognosis, with limited therapeutic options. The standard of treatment is the combination of gem and cisplatin; a meta-analysis conducted by Valle and collaborators demonstrated that this association gave a significant survival advantage, compared to gem alone (progression free survival, PFS, of 8 vs 6.7 months; overall survival, OS of 11.6 months vs 8.0 months) [6]. These data demonstrate the lack of effective therapies and the need of identifying alternative therapeutic approaches
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