ArticleMolecular cancer research : MCR2021
Mutant KRAS Downregulates the Receptor for Leukemia Inhibitory Factor (LIF) to Enhance a Signature of Glycolysis in Pancreatic Cancer and Lung Cancer.
Article in Molecular cancer research : MCR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 23 citations in OpenAlex.
- The regulatory roles of non-coding RNAs in aerobic glycolysis and therapeutic potential in pancreatic ductal adenocarcinoma.Annals of medicine · 2026Review
- Review
- Expression of LIFR in tumor and SHOC2, YAP1 in plasma mRNA as potential biomarkers in KRASScientific reports · 2026Article
- KRAS-driven cytokine-metabolic crosstalk shapes immune exclusion in pancreatic ductal adenocarcinoma.Frontiers in genetics · 2026Review
- Tumor exosomal miR-221-3p induces glycolysis through the LIFR/GLUT1 pathway to destroy the cerebral vascular endothelial cell barrier and promote breast cancer brain metastasis.Journal of translational medicine · 2025Article
- IFNγ and TNFα drive an inflammatory secretion profile in cancer-associated fibroblasts from human non-small cell lung cancer.FEBS letters · 2025Article
- The roles of KRAS in cancer metabolism, tumor microenvironment and clinical therapy.Molecular cancer · 2025Review
- SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis.JCI insight · 2023Article
- Role and mechanism of leukemia inhibitory factor receptor in cervical cancer invasion and metastasis.The Journal of international medical research · 2023Article
- STAT proteins in cancer: orchestration of metabolism.Nature reviews. Cancer · 2023Review
- Review
- Genetic architecture for skeletal muscle glycolytic potential in Chinese Erhualian pigs revealed by a genome-wide association study using 1.4M SNP array.Frontiers in genetics · 2023Article
- Pan-cancer analysis identifies LIFR as a prognostic and immunological biomarker for uterine corpus endometrial carcinoma.Frontiers in oncology · 2023Article
- A new immune signature for survival prediction and immune checkpoint molecules in non-small cell lung cancer.Frontiers in oncology · 2023Article
- 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
- Review
- Interaction between glycolysis‒cholesterol synthesis axis and tumor microenvironment reveal that gamma-glutamyl hydrolase suppresses glycolysis in colon cancer.Frontiers in immunology · 2022Article
- Long Noncoding RNAs and Circular RNAs in the Metabolic Reprogramming of Lung Cancer: Functions, Mechanisms, and Clinical Potential.Oxidative medicine and cellular longevity · 2022Review
- Harnessing Metabolic Reprogramming to Improve Cancer Immunotherapy.International journal of molecular sciences · 2021Review
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Pancreatic cancer is characterized by aberrant activity of oncogenic KRAS, which is mutated in 90% of pancreatic adenocarcinomas. Because KRAS itself is a challenging therapeutic target, we focused on understanding key signaling pathways driven by KRAS as a way to reveal dependencies that are amenable to therapeutic intervention. Analyses in primary human pancreatic cancers and model systems revealed that the receptor for the cytokine leukemia inhibitory factor (LIF) is downregulated by mutant KRAS. Furthermore, downregulation of the LIF receptor (LIFR) is necessary for KRAS-mediated neoplastic transformation. We found LIFR exerts inhibitory effects on KRAS-mediated transformation by inhibiting expression of the glucose transporter GLUT1, a key mediator of the enhanced glycolysis found in KRAS-driven malignancies. Decreased LIFR expression leads to increased GLUT1 as well as increases in glycolysis and mitochondrial respiration. The repression of GLUT1 by LIFR is mediated by the transcription factor STAT3, indicating a tumor-suppressive role for STAT3 within cancer cells with mutated KRAS. Finally, reflecting a clinically important tumor-suppressive role of LIFR, decreased LIFR expression correlates with shorter survival in pancreatic cancer patients with mutated KRAS. Similar findings were found in non-small cell lung cancers driven by mutated KRAS, suggesting that silencing LIFR is a generalized mechanism of KRAS-mediated cellular transformation. These results indicate that the LIFR/STAT3 pathway may mediate either tumor-promoting or tumor-suppressive signaling pathways depending on the genetic background of tumor cells, and may play diverse roles within other cells in the tumor microenvironment. IMPLICATIONS: Mutant KRAS drives downregulation of the receptor for LIF, thereby allowing an increase in expression of the glucose transporter GLUT1 and increases in glycolysis and mitochondrial respiration.
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