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Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells.
Di Matteo, Sabina; Nevi, Lorenzo; Overi, Diletta; Landolina, Nadine; Faccioli, Jessica; Giulitti, Federico; Napoletano, Chiara; Oddi, Andrea; Marziani, Augusto M; Costantini, Daniele; De Rose, Agostino M; Melandro, Fabio; Bragazzi, Maria C; Grazi, Gian Luca; Berloco, Pasquale B; Giuliante, Felice; Donato, Giuseppe; Moretta, Lorenzo; Carpino, Guido; Cardinale, Vincenzo; Gaudio, Eugenio; Alvaro, Domenico.
Afiliação
  • Di Matteo S; Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy. dimatteo.sabina@gmail.com.
  • Nevi L; Department of Immunology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. dimatteo.sabina@gmail.com.
  • Overi D; Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
  • Landolina N; Department of Biosciences, University of Milan, Milan, Italy.
  • Faccioli J; Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
  • Giulitti F; Department of Immunology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • Napoletano C; Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
  • Oddi A; Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
  • Marziani AM; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
  • Costantini D; Gastroenterology Unit, Regina Elena National Cancer Institute, Rome, Italy.
  • De Rose AM; Department of Information, Electronics and Telecommunications Engineering, Sapienza University of Rome, Rome, Italy.
  • Melandro F; Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
  • Bragazzi MC; Hepatobiliary Unit, Catholic University of the Sacred Heart School of Medicine, Rome, Italy.
  • Grazi GL; Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy.
  • Berloco PB; Medical-Surgical and Biotechnologies Sciences, Polo Pontino, Sapienza University of Rome, Rome, Italy.
  • Giuliante F; Gastroenterology Unit, Regina Elena National Cancer Institute, Rome, Italy.
  • Donato G; Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy.
  • Moretta L; Hepatobiliary Unit, Catholic University of the Sacred Heart School of Medicine, Rome, Italy.
  • Carpino G; Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
  • Cardinale V; Department of Immunology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • Gaudio E; Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy.
  • Alvaro D; Medical-Surgical and Biotechnologies Sciences, Polo Pontino, Sapienza University of Rome, Rome, Italy.
Sci Rep ; 11(1): 2557, 2021 01 28.
Article em En | MEDLINE | ID: mdl-33510179
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Colangiocarcinoma / Transição Epitelial-Mesenquimal / Neoplasias Hepáticas / Metformina Limite: Animals / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Colangiocarcinoma / Transição Epitelial-Mesenquimal / Neoplasias Hepáticas / Metformina Limite: Animals / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article