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Gene and microRNA modulation upon ET-743 treatment in a human intrahepatic cholangiocarcinoma paired patient derived xenograft and cell line

ABSTRACT: Gene and microRNA modulation upon ET-743 treatment in a human intrahepatic cholangiocarcinoma paired patient derived xenograft and cell line

PROVIDER: PRJNA335711 | ENA |

REPOSITORIES: ENA

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Gene and microRNA modulation upon ET-743 treatment in a human intrahepatic cholangiocarcinoma paired patient derived xenograft and cell line [miRNA expression]

Project description:Transcriptional profiling and microRNA profiling of paired PDX and derived cell line MT-CHC01 upon ET-743 treatement Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy with limited therapeutic options. ET-743 has a high antitumor activity in preclinical models of biliary tract carcinoma (BTC), being a promising alternative treatment. Here, we studied the effect of ET-743 at transcriptomic level on an ICC patient derived xenograft (PDX) and on the derived cell line, MT-CHC01. Further, putative targets of ET-743 were explored in the in vitro model. In vitro, ET-743 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, ET-743 affected ECM-receptor interaction, focal adhesion, complement and coagulation cascades, Hedgehog, MAPK, EGFR signaling via PIP3 pathway, and apoptosis. In MT-CHC01, 24 microRNAs were deregulated upon drug treatment. Only 5 microRNAs were perturbed by ET-743 in PDX; 2 up and 3 down-regulated. Among down- regulated genes, we selected SYK and LGALS1; their silencing caused a significantly reduction of migration, but did not affect proliferation in MT-CHC01 and WITT cells. In conclusion, we described that ET-743 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 ET-743.

2017-06-10 | GSE84938 | GEO

Gene and microRNA modulation upon ET-743 treatment in a human intrahepatic cholangiocarcinoma paired patient derived xenograft and cell line [gene expression]

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Effect of Crenigacestat treatment in xenograft model of HUCCT1 intrahepatic cholangiocarcinoma

Project description:Intrahepatic Cholangiocarcinoma (iCCA) is a difficult type of cancer to diagnose, extremely aggressive and resistant to therapeutic options with an increased incidence and mortality over time. The overexpression of Notch pathway is implicated in iCCA to create an ecosystem that drives the tumor aggressiveness. Specifically, Notch1 is overexpressed in iCCA tissue of patients, playing an important role on tumor growth. Our purpose was to investigate the effectiveness of Crenigacestat in in vivo experiments, using Hucct1 injected in CD1 mice to generate an iCCA xenograft mouse model. In the present study, in order to explore modulated factors and genes by treatment we performed a transcriptomic analysis validated by Western Blotting and qRT-PCR on iCCA tumor masses of xenograft mice. Our results indicate that the treatment significantly inhibited Notch1 and HES1 genes and proteins triggering a strong immune response. Nevertheless, moderate fibrosis was shown in this model which may have hindered response to therapy to promote tumor progression. We used microarray technology to understand the molecular mechanisms affected by Crenigacestat in HUCCT1 xenograft model of intraepatic cholangiocarcinoma.

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