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.

Diagnostic and prognostic value of microRNAs in cholangiocarcinoma: a systematic review and meta-analysis

“…miRNAs have been implicated in the pathogenesis of CCA 42 – 45 because upregulated miRNAs suggest an oncogenic role and downregulation of miRNAs may be suppressive, so dysregulated miRNAs are correlated with the adverse clinical features, diminished survival, and poor prognosis of CCA patients. 46 Selaru et al 36 proved that miR-21 was oncogenic by inhibiting PDCD4 and TIMP3 suppressor genes in the biliary tree.…”

miRNA and lncRNA as biomarkers in cholangiocarcinoma(CCA)

“…Taken together, miRNA-29a/205/221 show promises serving as tissue biomarkers of chemosensitivity in CCA patients. Furthermore, trabectedin, an anti-metastatic agent in CCA has been found to inhibit metastasis via downregulating the expression of gene SYK and LGALS1 [ 76 ]. These two genes are the direct targets of certain miRNAs such as MiR-21-3p, miR-21-5p and miR-31-3p and miR-1207-5p, miR-1225-5p separately, suggesting the overexpression of these miRNAs is closely associated with the effectiveness of trabectedin [ 76 ].…”

Integration of MRI and MRS approaches to monitor molecular imaging and metabolomic effects of trabectedin on a preclinical ovarian cancer model

“…The tumor growth arrest was associated with an about 50% reduction of HER2 mRNA and protein expression levels, as well as with a drop in the intracellular PCho content in SKOV3.ip cells. Several studies have shown that Trab induced a down‐modulation of mitogen‐activated protein kinase and EGFR signaling in cancer cell lines and patient‐derived xenografts and AKT–mTOR signaling in EOC . Therefore, we hypothesize that the decrease of tCho and PCho following Trab treatment might indicate a down‐modulation of oncogenic signaling and therefore reduced cell proliferation …”