학술논문
Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells
Document Type
article
Author
Sabina Di Matteo; Lorenzo Nevi; Diletta Overi; Nadine Landolina; Jessica Faccioli; Federico Giulitti; Chiara Napoletano; Andrea Oddi; Augusto M. Marziani; Daniele Costantini; Agostino M. De Rose; Fabio Melandro; Maria C. Bragazzi; Gian Luca Grazi; Pasquale B. Berloco; Felice Giuliante; Giuseppe Donato; Lorenzo Moretta; Guido Carpino; Vincenzo Cardinale; Eugenio Gaudio; Domenico Alvaro
Source
Scientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
Subject
Language
English
ISSN
2045-2322
Abstract
Abstract Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with marked resistance to chemotherapeutics without therapies. The tumour microenvironment of iCCA is enriched of Cancer-Stem-Cells expressing Epithelial-to-Mesenchymal Transition (EMT) traits, being these features associated with aggressiveness and drug resistance. Treatment with the anti-diabetic drug Metformin, has been recently associated with reduced incidence of iCCA. We aimed to evaluate the anti-cancerogenic effects of Metformin in vitro and in vivo on primary cultures of human iCCA. Our results showed that Metformin inhibited cell proliferation and induced dose- and time-dependent apoptosis of iCCA. The migration and invasion of iCCA cells in an extracellular bio-matrix was also significantly reduced upon treatments. Metformin increased the AMPK and FOXO3 and induced phosphorylation of activating FOXO3 in iCCA cells. After 12 days of treatment, a marked decrease of mesenchymal and EMT genes and an increase of epithelial genes were observed. After 2 months of treatment, in order to simulate chronic administration, Cytokeratin-19 positive cells constituted the majority of cell cultures paralleled by decreased Vimentin protein expression. Subcutaneous injection of iCCA cells previously treated with Metformin, in Balb/c-nude mice failed to induce tumour development. In conclusion, Metformin reverts the mesenchymal and EMT traits in iCCA by activating AMPK-FOXO3 related pathways suggesting it might have therapeutic implications.