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Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation

Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation
Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation
Cholangiocarcinoma is an aggressive, strongly chemoresistant liver malignancy. Leukemia inhibitory factor (LIF), an IL-6 family cytokine, promotes progression of various carcinomas. To investigate the role of LIF in cholangiocarcinoma, we evaluated the expression of LIF and its receptor (LIFR) in human samples. LIF secretion and LIFR expression were assessed in established and primary human cholangiocarcinoma cell lines. In cholangiocarcinoma cells, we tested LIF effects on proliferation, invasion, stem cell-like phenotype, chemotherapy-induced apoptosis (gemcitabine+cisplatin), expression levels of pro-apoptotic (Bax) and anti-apoptotic (Mcl-1) proteins, with/without PI3K inhibition, and of pSTAT3, pERK1/2, pAKT. LIF effect on chemotherapy-induced apoptosis was evaluated after LIFR silencing and Mcl-1 inactivation. Results show that LIF and LIFR expression were higher in neoplastic than in control cholangiocytes; LIF was also expressed by tumor stromal cells. LIF had no effects on cholangiocarcinoma cell proliferation, invasion, and stemness signatures, whilst it counteracted drug-induced apoptosis. Upon LIF stimulation, decreased apoptosis was associated with Mcl-1 and pAKT up-regulation and abolished by PI3K inhibition. LIFR silencing and Mcl-1 blockade restored drug-induced apoptosis. In conclusion, autocrine and paracrine LIF signaling promote chemoresistance in cholangiocarcinoma by up-regulating Mcl-1 via a novel STAT3- and MAPK-independent, PI3K/AKT-dependent pathway. Targeting LIF signaling may increase CCA responsiveness to chemotherapy.
cholangiocarcinoma, leukemia inhibitory factor, chemoresistance, Mcl-1, phosphatidylinositol-3 kinase
1949-2553
1-13
Morton, Stuart Duncan
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Cadamuro, Massimiliano
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Brivio, Simone
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Vismara, Marta
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Stecca, Tommaso
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Massani, Marco
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Bassi, Nicolò
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Furlanetto, Alberto
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Joplin, Ruth Elizabeth
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Floreani, Annarosa
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Fabris, Luca
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Strazzabosco, Mario
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Morton, Stuart Duncan
7545cf7d-15a6-43cc-9949-41ece1749fef
Cadamuro, Massimiliano
eee3861c-58b8-43a4-99d2-24f488b45eae
Brivio, Simone
01a49604-5914-4435-8a44-66d4bf44e74b
Vismara, Marta
c72b7c72-93e5-416e-856a-102e52dc0843
Stecca, Tommaso
196ca669-5540-4216-883d-ed9b32ee5ac8
Massani, Marco
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Bassi, Nicolò
0b829168-b99e-4258-8cf6-9f7136cc9d58
Furlanetto, Alberto
d909992a-86f2-4645-b3bc-18037494cd81
Joplin, Ruth Elizabeth
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Floreani, Annarosa
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Fabris, Luca
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Strazzabosco, Mario
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Morton, Stuart Duncan, Cadamuro, Massimiliano, Brivio, Simone, Vismara, Marta, Stecca, Tommaso, Massani, Marco, Bassi, Nicolò, Furlanetto, Alberto, Joplin, Ruth Elizabeth, Floreani, Annarosa, Fabris, Luca and Strazzabosco, Mario (2015) Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation. Oncotarget, 1-13. (doi:10.18632/oncotarget.4482). (PMID:26296968)

Record type: Article

Abstract

Cholangiocarcinoma is an aggressive, strongly chemoresistant liver malignancy. Leukemia inhibitory factor (LIF), an IL-6 family cytokine, promotes progression of various carcinomas. To investigate the role of LIF in cholangiocarcinoma, we evaluated the expression of LIF and its receptor (LIFR) in human samples. LIF secretion and LIFR expression were assessed in established and primary human cholangiocarcinoma cell lines. In cholangiocarcinoma cells, we tested LIF effects on proliferation, invasion, stem cell-like phenotype, chemotherapy-induced apoptosis (gemcitabine+cisplatin), expression levels of pro-apoptotic (Bax) and anti-apoptotic (Mcl-1) proteins, with/without PI3K inhibition, and of pSTAT3, pERK1/2, pAKT. LIF effect on chemotherapy-induced apoptosis was evaluated after LIFR silencing and Mcl-1 inactivation. Results show that LIF and LIFR expression were higher in neoplastic than in control cholangiocytes; LIF was also expressed by tumor stromal cells. LIF had no effects on cholangiocarcinoma cell proliferation, invasion, and stemness signatures, whilst it counteracted drug-induced apoptosis. Upon LIF stimulation, decreased apoptosis was associated with Mcl-1 and pAKT up-regulation and abolished by PI3K inhibition. LIFR silencing and Mcl-1 blockade restored drug-induced apoptosis. In conclusion, autocrine and paracrine LIF signaling promote chemoresistance in cholangiocarcinoma by up-regulating Mcl-1 via a novel STAT3- and MAPK-independent, PI3K/AKT-dependent pathway. Targeting LIF signaling may increase CCA responsiveness to chemotherapy.

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Accepted/In Press date: 8 July 2015
Published date: 20 July 2015
Keywords: cholangiocarcinoma, leukemia inhibitory factor, chemoresistance, Mcl-1, phosphatidylinositol-3 kinase
Organisations: Medical Education

Identifiers

Local EPrints ID: 382370
URI: http://eprints.soton.ac.uk/id/eprint/382370
ISSN: 1949-2553
PURE UUID: 5b86706f-7d8b-4bd1-9008-90cdae6d45fd
ORCID for Stuart Duncan Morton: ORCID iD orcid.org/0000-0002-5921-4869

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Date deposited: 29 Oct 2015 11:51
Last modified: 01 Oct 2019 00:33

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Contributors

Author: Massimiliano Cadamuro
Author: Simone Brivio
Author: Marta Vismara
Author: Tommaso Stecca
Author: Marco Massani
Author: Nicolò Bassi
Author: Alberto Furlanetto
Author: Ruth Elizabeth Joplin
Author: Annarosa Floreani
Author: Luca Fabris
Author: Mario Strazzabosco

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