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.
Highlights
Cholangiocarcinoma (CCA) is a highly aggressive cancer arising from epithelial cells lining intrahepatic or extrahepatic bile ducts
Results show that Leukemia inhibitory factor (LIF) and LIF and its receptor (LIFR) expression were higher in neoplastic than in control cholangiocytes; LIF was expressed by tumor stromal cells
By categorizing the CCA areas, a significantly higher extent of LIF staining in ‘ductular-like’ than in ‘mucin-producing’ tumoral bile ducts was determined (Supplementary Figure 1A, 1C); in contrast, no significant differences in the extent of LIFR staining were found between the two CCA subtypes (Supplementary Figure 1B, 1C)
Summary
Cholangiocarcinoma (CCA) is a highly aggressive cancer arising from epithelial cells lining intrahepatic (iCCA) or extrahepatic (eCCA) bile ducts. Resection can only be offered to a minority of patients (20–40%) because of a propensity for early intrahepatic www.impactjournals.com/oncotarget or lymph node metastatic dissemination, whereas liver transplant is available only for carefully selected cases in a few, highly-specialized liver centers [2, 3]. Both procedures are further complicated by high rates of recurrence [2, 3]. A recent study shows that combined administration of gemcitabine (GEM) and cisplatin (CDDP) in the treatment of advanced CCA increases patient overall survival [6] of about four months compared with patients treated with GEM alone [6]
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