Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells
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 associa...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/24995b33e4b34af8bdf9f9dd2444c0b4 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:24995b33e4b34af8bdf9f9dd2444c0b4 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:24995b33e4b34af8bdf9f9dd2444c0b42021-12-02T10:48:21ZMetformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells10.1038/s41598-021-81172-02045-2322https://doaj.org/article/24995b33e4b34af8bdf9f9dd2444c0b42021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81172-0https://doaj.org/toc/2045-2322Abstract 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.Sabina Di MatteoLorenzo NeviDiletta OveriNadine LandolinaJessica FaccioliFederico GiulittiChiara NapoletanoAndrea OddiAugusto M. MarzianiDaniele CostantiniAgostino M. De RoseFabio MelandroMaria C. BragazziGian Luca GraziPasquale B. BerlocoFelice GiulianteGiuseppe DonatoLorenzo MorettaGuido CarpinoVincenzo CardinaleEugenio GaudioDomenico AlvaroNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q 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 Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells |
| description |
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. |
| format |
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 |
| author_facet |
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 |
| author_sort |
Sabina Di Matteo |
| title |
Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells |
| title_short |
Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells |
| title_full |
Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells |
| title_fullStr |
Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells |
| title_full_unstemmed |
Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells |
| title_sort |
metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/24995b33e4b34af8bdf9f9dd2444c0b4 |
| work_keys_str_mv |
AT sabinadimatteo metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT lorenzonevi metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT dilettaoveri metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT nadinelandolina metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT jessicafaccioli metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT federicogiulitti metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT chiaranapoletano metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT andreaoddi metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT augustommarziani metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT danielecostantini metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT agostinomderose metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT fabiomelandro metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT mariacbragazzi metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT gianlucagrazi metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT pasqualebberloco metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT felicegiuliante metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT giuseppedonato metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT lorenzomoretta metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT guidocarpino metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT vincenzocardinale metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT eugeniogaudio metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells AT domenicoalvaro metforminexertsanticancerogeniceffectsandreversesepithelialtomesenchymaltransitiontraitinprimaryhumanintrahepaticcholangiocarcinomacells |
| _version_ |
1718396636300836864 |