Gene and microRNA modulation upon trabectedin treatment in a human intrahepatic cholangiocarcinoma paired patient derived xenograft and cell line

Oncotarget. 2016 Dec 27;7(52):86766-86780. doi: 10.18632/oncotarget.13575.


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.

Keywords: Intrahepatic cholangiocarcinoma; microRNA; microarray; silencing; trabectedin.

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Bile Duct Neoplasms / drug therapy*
  • Bile Duct Neoplasms / genetics
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cholangiocarcinoma / drug therapy*
  • Cholangiocarcinoma / genetics
  • Cluster Analysis
  • Dioxoles / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Ontology
  • Humans
  • Mice
  • MicroRNAs / genetics*
  • Tetrahydroisoquinolines / pharmacology*
  • Trabectedin
  • Transcriptome / drug effects
  • Xenograft Model Antitumor Assays*


  • Antineoplastic Agents, Alkylating
  • Dioxoles
  • MicroRNAs
  • Tetrahydroisoquinolines
  • Trabectedin