ArticleOncotarget2015
Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 58 citations in OpenAlex.
- Methylmalonic acid as a ferroptosis-derived danger signal: activation of the PI3K-NF-κB pathway drives M1 macrophage polarization in renal ischemia-reperfusion injury.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- EGFR-mutant transformed small cell lung cancer harbors intratumoral heterogeneity targetable with MEK inhibitor combination therapy.JCI insight · 2026Article
- MCL-1 as a tumor microenvironment-linked survival node in cholangiocarcinoma.Frontiers in oncology · 2026Article
- Cancer-Associated Fibroblasts Interact with Schwann Cells for Tumor Perineural Invasion by Oral Squamous Cell Carcinoma.Neuroscience bulletin · 2025Article
- Significance of LIF/LIFR Signaling in the Progression of Obesity-Driven Triple-Negative Breast Cancer.Cancers · 2024Article
- Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis.NPJ precision oncology · 2024Article
- The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling.International journal of molecular sciences · 2023Article
- New perspectives in cancer immunotherapy: targeting IL-6 cytokine family.Journal for immunotherapy of cancer · 2023Review
- MUG CCArly: A Novel Autologous 3D Cholangiocarcinoma Model Presents an Increased Angiogenic Potential.Cancers · 2023Article
- Identification of a necroptosis-related gene signature as a novel prognostic biomarker of cholangiocarcinoma.Frontiers in immunology · 2023Article
- Article
- The Pleiotropic role, functions and targeted therapies of LIF/LIFR axis in cancer: Old spectacles with new insights.Biochimica et biophysica acta. Reviews on cancer · 2022Review
- Targeting LIF/LIFR signaling in cancer.Genes & diseases · 2022Review
- Gp130-Mediated STAT3 Activation Contributes to the Aggressiveness of Pancreatic Cancer throughCancers · 2022Article
- Leukemia Inhibitory Factor Promotes Survival of Hematopoietic Progenitors Ex Vivo and Is Post-Translationally Regulated by DPP4.Stem cells (Dayton, Ohio) · 2022Article
- Review
- Leukemia Inhibitory Factor: An Important Cytokine in Pathologies and Cancer.Biomolecules · 2022Review
- Elevated expression of LIF predicts a poor prognosis and promotes cell migration and invasion of clear cell renal cell carcinoma.Frontiers in oncology · 2022Article
- Overcome Drug Resistance in Cholangiocarcinoma: New Insight Into Mechanisms and Refining the Preclinical Experiment Models.Frontiers in oncology · 2022Review
- Ferroptosis in Intrahepatic Cholangiocarcinoma:Frontiers in medicine · 2022Article
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
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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