BioProject

Intrahepatic cholangiocarcinoma (ICC) is one of the most lethal liver cancers. More...

Intrahepatic cholangiocarcinoma (ICC) is one of the most lethal liver cancers. The late diagnosis as well as the resistance to chemotherapy concurred to the scarce outfit of this malignancy. Even the improvement of the knowledge and, as consequence, of the broad spectrum of alternative therapies available (i.e. targeted, immune checkpoint inhibitors), the survival and the quality of life remain poor. The phenomenon of resistance is not still clear. Here, we established one gemcitabine, GEM, (the standard therapy in ICC) resistant cell line, named MTCHC01R1.5, obtained by a gradual exposure to GEM for 9 months (up to 1.5 µM) of the sensible counterpart MT-CHC01. We biologically and molecularly characterized this cell line comparing its behavior with its parental cell line. The drug resistance is irreversible, even if cells are treated with high doses of GEM. They grew slowly, both in vitro and in vivo, and no differences are highlighted in terms of migration and invasion. GEM resistance promoted a multi drug resistance development, but the drug prediction analysis showed that paclitaxel and doxycycline could overcome GEM resistance, as confirmed by cell viability assay. There is a global enrichment of up-regulated genes involved in the regulation of cell cycle and in DNA related process. The down-regulated genes are involved in response to stimuli, and xenobiotic metabolism, and angiogenesis. A deregulation of more than 20 genes related to drug resistance and epithelial to mesenchymal transition (EMT) was found. The trend in expression of 9 genes related to resistance is confirmed in a primary cell culture. In conclusion, we characterized a new Italian GEM resistance ICC model which could be exploited either to study the mechanism of resistance or to explore new therapies. Overall design: Comparison between the parental cell line MT-CHC01 and its resistant counterpart MT-CHC01R1.5 Less...