Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression

O Erice; I Labiano; A Arbelaiz; A Santos-Laso; P Munoz-Garrido; R Jimenez-Agüero; P Olaizola; A Caro-Maldonado; N Martín-Martín; A Carracedo; E Lozano; J J Marin; C J O'Rourke; J B Andersen; J Llop; V Gómez-Vallejo; D Padro; A Martin; M Marzioni; L Adorini; M Trauner; L Bujanda; M J Perugorria; J M Banales

doi:10.1016/j.bbadis.2017.08.016

Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression

O Erice, I Labiano, A Arbelaiz, A Santos-Laso, P Munoz-Garrido, R Jimenez-Agüero, P Olaizola, A Caro-Maldonado, N Martín-Martín, A Carracedo, E Lozano, J J Marin, C J O'Rourke, J B Andersen, J Llop, V Gómez-Vallejo, D Padro, A Martin, M Marzioni, L AdoriniM Trauner, L Bujanda, M J Perugorria, J M Banales

25 Citations (Scopus)

Abstract

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated.

METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro.

RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism.

CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.

Original language	English
Journal	B B A - Reviews on Cancer
Volume	1864
Issue number	4, Part B
Pages (from-to)	1335-1344
ISSN	0006-3002
DOIs	https://doi.org/10.1016/j.bbadis.2017.08.016
Publication status	Published - Apr 2018

Keywords

Journal Article

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10.1016/j.bbadis.2017.08.016

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Erice, O., Labiano, I., Arbelaiz, A., Santos-Laso, A., Munoz-Garrido, P., Jimenez-Agüero, R., Olaizola, P., Caro-Maldonado, A., Martín-Martín, N., Carracedo, A., Lozano, E., Marin, J. J., O'Rourke, C. J., Andersen, J. B., Llop, J., Gómez-Vallejo, V., Padro, D., Martin, A., Marzioni, M., ... Banales, J. M. (2018). Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression. B B A - Reviews on Cancer, 1864(4, Part B), 1335-1344. https://doi.org/10.1016/j.bbadis.2017.08.016

Erice, O, Labiano, I, Arbelaiz, A, Santos-Laso, A, Munoz-Garrido, P, Jimenez-Agüero, R, Olaizola, P, Caro-Maldonado, A, Martín-Martín, N, Carracedo, A, Lozano, E, Marin, JJ, O'Rourke, CJ , Andersen, JB, Llop, J, Gómez-Vallejo, V, Padro, D, Martin, A, Marzioni, M, Adorini, L, Trauner, M, Bujanda, L, Perugorria, MJ & Banales, JM 2018, 'Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression', B B A - Reviews on Cancer, vol. 1864, no. 4, Part B, pp. 1335-1344. https://doi.org/10.1016/j.bbadis.2017.08.016

@article{7c56d08cb88147fda5f07099c7ac1986,

title = "Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression",

abstract = "BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated.METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro.RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism.CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.",

keywords = "Journal Article",

author = "O Erice and I Labiano and A Arbelaiz and A Santos-Laso and P Munoz-Garrido and R Jimenez-Ag{\"u}ero and P Olaizola and A Caro-Maldonado and N Mart{\'i}n-Mart{\'i}n and A Carracedo and E Lozano and Marin, {J J} and O'Rourke, {C J} and Andersen, {J B} and J Llop and V G{\'o}mez-Vallejo and D Padro and A Martin and M Marzioni and L Adorini and M Trauner and L Bujanda and Perugorria, {M J} and Banales, {J M}",

note = "Copyright {\textcopyright} 2017. Published by Elsevier B.V.",

year = "2018",

month = apr,

doi = "10.1016/j.bbadis.2017.08.016",

language = "English",

volume = "1864",

pages = "1335--1344",

journal = "B B A - Reviews on Cancer",

issn = "0006-3002",

publisher = "Elsevier",

number = "4, Part B",

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TY - JOUR

T1 - Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression

AU - Erice, O

AU - Labiano, I

AU - Arbelaiz, A

AU - Santos-Laso, A

AU - Munoz-Garrido, P

AU - Jimenez-Agüero, R

AU - Olaizola, P

AU - Caro-Maldonado, A

AU - Martín-Martín, N

AU - Carracedo, A

AU - Lozano, E

AU - Marin, J J

AU - O'Rourke, C J

AU - Andersen, J B

AU - Llop, J

AU - Gómez-Vallejo, V

AU - Padro, D

AU - Martin, A

AU - Marzioni, M

AU - Adorini, L

AU - Trauner, M

AU - Bujanda, L

AU - Perugorria, M J

AU - Banales, J M

PY - 2018/4

Y1 - 2018/4

N2 - BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated.METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro.RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism.CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.

AB - BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated.METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro.RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism.CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.

KW - Journal Article

U2 - 10.1016/j.bbadis.2017.08.016

DO - 10.1016/j.bbadis.2017.08.016

M3 - Journal article

C2 - 28916388

SN - 0006-3002

VL - 1864

SP - 1335

EP - 1344

JO - B B A - Reviews on Cancer

JF - B B A - Reviews on Cancer

IS - 4, Part B

ER -

Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression

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