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...
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Autor*in:	Sabina Di Matteo [verfasserIn] Lorenzo Nevi [verfasserIn] Diletta Overi [verfasserIn] Nadine Landolina [verfasserIn] Jessica Faccioli [verfasserIn] Federico Giulitti [verfasserIn] Chiara Napoletano [verfasserIn] Andrea Oddi [verfasserIn] Augusto M. Marziani [verfasserIn] Daniele Costantini [verfasserIn] Agostino M. De Rose [verfasserIn] Fabio Melandro [verfasserIn] Maria C. Bragazzi [verfasserIn] Gian Luca Grazi [verfasserIn] Pasquale B. Berloco [verfasserIn] Felice Giuliante [verfasserIn] Giuseppe Donato [verfasserIn] Lorenzo Moretta [verfasserIn] Guido Carpino [verfasserIn] Vincenzo Cardinale [verfasserIn] Eugenio Gaudio [verfasserIn] Domenico Alvaro [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Übergeordnetes Werk:	In: Scientific Reports - Nature Portfolio, 2011, 11(2021), 1, Seite 18
Übergeordnetes Werk:	volume:11 ; year:2021 ; number:1 ; pages:18

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41598-021-81172-0

Katalog-ID:	DOAJ07489465X

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allfields	10.1038/s41598-021-81172-0 doi (DE-627)DOAJ07489465X (DE-599)DOAJ24995b33e4b34af8bdf9f9dd2444c0b4 DE-627 ger DE-627 rakwb eng Sabina Di Matteo verfasserin aut Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Lorenzo Nevi verfasserin aut Diletta Overi verfasserin aut Nadine Landolina verfasserin aut Jessica Faccioli verfasserin aut Federico Giulitti verfasserin aut Chiara Napoletano verfasserin aut Andrea Oddi verfasserin aut Augusto M. Marziani verfasserin aut Daniele Costantini verfasserin aut Agostino M. De Rose verfasserin aut Fabio Melandro verfasserin aut Maria C. Bragazzi verfasserin aut Gian Luca Grazi verfasserin aut Pasquale B. Berloco verfasserin aut Felice Giuliante verfasserin aut Giuseppe Donato verfasserin aut Lorenzo Moretta verfasserin aut Guido Carpino verfasserin aut Vincenzo Cardinale verfasserin aut Eugenio Gaudio verfasserin aut Domenico Alvaro verfasserin aut In Scientific Reports Nature Portfolio, 2011 11(2021), 1, Seite 18 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:11 year:2021 number:1 pages:18 https://doi.org/10.1038/s41598-021-81172-0 kostenfrei https://doaj.org/article/24995b33e4b34af8bdf9f9dd2444c0b4 kostenfrei https://doi.org/10.1038/s41598-021-81172-0 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 18
spelling	10.1038/s41598-021-81172-0 doi (DE-627)DOAJ07489465X (DE-599)DOAJ24995b33e4b34af8bdf9f9dd2444c0b4 DE-627 ger DE-627 rakwb eng Sabina Di Matteo verfasserin aut Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Lorenzo Nevi verfasserin aut Diletta Overi verfasserin aut Nadine Landolina verfasserin aut Jessica Faccioli verfasserin aut Federico Giulitti verfasserin aut Chiara Napoletano verfasserin aut Andrea Oddi verfasserin aut Augusto M. Marziani verfasserin aut Daniele Costantini verfasserin aut Agostino M. De Rose verfasserin aut Fabio Melandro verfasserin aut Maria C. Bragazzi verfasserin aut Gian Luca Grazi verfasserin aut Pasquale B. Berloco verfasserin aut Felice Giuliante verfasserin aut Giuseppe Donato verfasserin aut Lorenzo Moretta verfasserin aut Guido Carpino verfasserin aut Vincenzo Cardinale verfasserin aut Eugenio Gaudio verfasserin aut Domenico Alvaro verfasserin aut In Scientific Reports Nature Portfolio, 2011 11(2021), 1, Seite 18 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:11 year:2021 number:1 pages:18 https://doi.org/10.1038/s41598-021-81172-0 kostenfrei https://doaj.org/article/24995b33e4b34af8bdf9f9dd2444c0b4 kostenfrei https://doi.org/10.1038/s41598-021-81172-0 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 18
allfields_unstemmed	10.1038/s41598-021-81172-0 doi (DE-627)DOAJ07489465X (DE-599)DOAJ24995b33e4b34af8bdf9f9dd2444c0b4 DE-627 ger DE-627 rakwb eng Sabina Di Matteo verfasserin aut Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Lorenzo Nevi verfasserin aut Diletta Overi verfasserin aut Nadine Landolina verfasserin aut Jessica Faccioli verfasserin aut Federico Giulitti verfasserin aut Chiara Napoletano verfasserin aut Andrea Oddi verfasserin aut Augusto M. Marziani verfasserin aut Daniele Costantini verfasserin aut Agostino M. De Rose verfasserin aut Fabio Melandro verfasserin aut Maria C. Bragazzi verfasserin aut Gian Luca Grazi verfasserin aut Pasquale B. Berloco verfasserin aut Felice Giuliante verfasserin aut Giuseppe Donato verfasserin aut Lorenzo Moretta verfasserin aut Guido Carpino verfasserin aut Vincenzo Cardinale verfasserin aut Eugenio Gaudio verfasserin aut Domenico Alvaro verfasserin aut In Scientific Reports Nature Portfolio, 2011 11(2021), 1, Seite 18 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:11 year:2021 number:1 pages:18 https://doi.org/10.1038/s41598-021-81172-0 kostenfrei https://doaj.org/article/24995b33e4b34af8bdf9f9dd2444c0b4 kostenfrei https://doi.org/10.1038/s41598-021-81172-0 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 18
allfieldsGer	10.1038/s41598-021-81172-0 doi (DE-627)DOAJ07489465X (DE-599)DOAJ24995b33e4b34af8bdf9f9dd2444c0b4 DE-627 ger DE-627 rakwb eng Sabina Di Matteo verfasserin aut Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Lorenzo Nevi verfasserin aut Diletta Overi verfasserin aut Nadine Landolina verfasserin aut Jessica Faccioli verfasserin aut Federico Giulitti verfasserin aut Chiara Napoletano verfasserin aut Andrea Oddi verfasserin aut Augusto M. Marziani verfasserin aut Daniele Costantini verfasserin aut Agostino M. De Rose verfasserin aut Fabio Melandro verfasserin aut Maria C. Bragazzi verfasserin aut Gian Luca Grazi verfasserin aut Pasquale B. Berloco verfasserin aut Felice Giuliante verfasserin aut Giuseppe Donato verfasserin aut Lorenzo Moretta verfasserin aut Guido Carpino verfasserin aut Vincenzo Cardinale verfasserin aut Eugenio Gaudio verfasserin aut Domenico Alvaro verfasserin aut In Scientific Reports Nature Portfolio, 2011 11(2021), 1, Seite 18 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:11 year:2021 number:1 pages:18 https://doi.org/10.1038/s41598-021-81172-0 kostenfrei https://doaj.org/article/24995b33e4b34af8bdf9f9dd2444c0b4 kostenfrei https://doi.org/10.1038/s41598-021-81172-0 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 18
allfieldsSound	10.1038/s41598-021-81172-0 doi (DE-627)DOAJ07489465X (DE-599)DOAJ24995b33e4b34af8bdf9f9dd2444c0b4 DE-627 ger DE-627 rakwb eng Sabina Di Matteo verfasserin aut Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Lorenzo Nevi verfasserin aut Diletta Overi verfasserin aut Nadine Landolina verfasserin aut Jessica Faccioli verfasserin aut Federico Giulitti verfasserin aut Chiara Napoletano verfasserin aut Andrea Oddi verfasserin aut Augusto M. Marziani verfasserin aut Daniele Costantini verfasserin aut Agostino M. De Rose verfasserin aut Fabio Melandro verfasserin aut Maria C. Bragazzi verfasserin aut Gian Luca Grazi verfasserin aut Pasquale B. Berloco verfasserin aut Felice Giuliante verfasserin aut Giuseppe Donato verfasserin aut Lorenzo Moretta verfasserin aut Guido Carpino verfasserin aut Vincenzo Cardinale verfasserin aut Eugenio Gaudio verfasserin aut Domenico Alvaro verfasserin aut In Scientific Reports Nature Portfolio, 2011 11(2021), 1, Seite 18 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:11 year:2021 number:1 pages:18 https://doi.org/10.1038/s41598-021-81172-0 kostenfrei https://doaj.org/article/24995b33e4b34af8bdf9f9dd2444c0b4 kostenfrei https://doi.org/10.1038/s41598-021-81172-0 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 18
language	English
source	In Scientific Reports 11(2021), 1, Seite 18 volume:11 year:2021 number:1 pages:18
sourceStr	In Scientific Reports 11(2021), 1, Seite 18 volume:11 year:2021 number:1 pages:18
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Medicine R Science Q
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container_title	Scientific Reports
authorswithroles_txt_mv	Sabina Di Matteo @@aut@@ Lorenzo Nevi @@aut@@ Diletta Overi @@aut@@ Nadine Landolina @@aut@@ Jessica Faccioli @@aut@@ Federico Giulitti @@aut@@ Chiara Napoletano @@aut@@ Andrea Oddi @@aut@@ Augusto M. Marziani @@aut@@ Daniele Costantini @@aut@@ Agostino M. De Rose @@aut@@ Fabio Melandro @@aut@@ Maria C. Bragazzi @@aut@@ Gian Luca Grazi @@aut@@ Pasquale B. Berloco @@aut@@ Felice Giuliante @@aut@@ Giuseppe Donato @@aut@@ Lorenzo Moretta @@aut@@ Guido Carpino @@aut@@ Vincenzo Cardinale @@aut@@ Eugenio Gaudio @@aut@@ Domenico Alvaro @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	663366712
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language_de	englisch
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author	Sabina Di Matteo
spellingShingle	Sabina Di Matteo misc Medicine misc R misc Science misc Q Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells
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topic_title	Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells
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title	Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells
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title_full	Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells
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author_browse	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
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title_sort	metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells
title_auth	Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells
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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells
url	https://doi.org/10.1038/s41598-021-81172-0 https://doaj.org/article/24995b33e4b34af8bdf9f9dd2444c0b4 https://doaj.org/toc/2045-2322
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author2	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
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Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells

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