Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12857/116498
Title: Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation
Authors: Morton, Stuart Duncan 
Cadamuro, Massimiliano 
Brivio, Simone
Vismara, Marta 
Stecca, Tommaso 
Massani, Marco 
Bassi, Nicolò
Furlanetto, Alberto
Joplin, Ruth Elizabeth
Floreani, Annarosa 
Fabris, Luca
Strazzabosco, Mario
Keywords: Mcl-1;chemoresistance;cholangiocarcinoma;leukemia inhibitory factor;phosphatidylinositol-3 kinase
Keywords Plus: GROWTH-FACTOR;CARCINOMA-CELLS;CANCER;EXPRESSION;LIF;INTERLEUKIN-6;MANAGEMENT;DIAGNOSIS;SURVIVAL;PATHWAY
Mesh headings: Antineoplastic Agents;Apoptosis;Leukemia Inhibitory Factor;Myeloid Cell Leukemia Sequence 1 Protein;Phosphatidylinositol 3-Kinases;Proto-Oncogene Proteins c-akt
Secondary Mesh headings: Bile Duct Neoplasms;Blotting, Western;Cell Line, Tumor;Cholangiocarcinoma;Cisplatin;Deoxycytidine;Gene Expression Regulation, Neoplastic;Humans;Leukemia Inhibitory Factor Receptor alpha Subunit;Microscopy, Fluorescence;RNA Interference;Reverse Transcriptase Polymerase Chain Reaction;Signal Transduction
Issue Date: 22-Sep-2015
Publisher: IMPACT JOURNALS LLC
Journal: Oncotarget 
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.
URI: http://hdl.handle.net/20.500.12857/116498
DOI: 10.18632/oncotarget.4482
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