ArticleBMC pulmonary medicine2021
EML4-ALK-mediated activation of the JAK2-STAT pathway is critical for non-small cell lung cancer transformation.
Article in BMC pulmonary medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 24 citations in OpenAlex.
- Three decades of anaplastic lymphoma kinase: from physiological roles to cancer and immune evasion.Cancer metastasis reviews · 2026Review
- ALK rearrangements and resistance mutations in non-small cell lung cancer: molecular mechanisms and therapeutic implications.Cancer chemotherapy and pharmacology · 2026Review
- Crizotinib attenuates bleomycin-induced pulmonary fibrosis via regulating fibroblast activation.Journal of thoracic disease · 2026Article
- DUSP7 Overexpression Suppresses Lung Adenocarcinoma Cell Proliferation, Invasion, and M2 Macrophage Polarization Through JAK2/STAT3 Pathway Inhibition.Applied biochemistry and biotechnology · 2026Article
- Preclinical Prediction of Resistance Mutations and Proposal of Sequential Treatment Strategies for ALK-positive Lung Cancer Using Next-generation ALK Inhibitors.Pharmaceutical research · 2025Article
- RNase1-driven ALK-activation is an oncogenic driver and therapeutic target in non-small cell lung cancer.Signal transduction and targeted therapy · 2025Article
- Article
- New advances in understanding the mechanisms and treatment challenges of ALK-targeted therapy resistance in lung cancer.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer.Cell death & disease · 2024Article
- Efficacy of alectinib in lung adenocarcinoma patients with different anaplastic lymphoma kinase (Translational lung cancer research · 2023Article
- ALK-positive lung cancer: a moving target.Nature cancer · 2023Review
- Lack of SIRP-alpha reduces lung cancer growth in mice by promoting anti-tumour ability of macrophages and neutrophils.Cell proliferation · 2023Article
- Neutrophil infiltration associated genes on the prognosis and tumor immune microenvironment of lung adenocarcinoma.Frontiers in immunology · 2023Article
- EML4-ALK fusion gene in non-small cell lung cancer.Oncology letters · 2022Review
- Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer.Cancers · 2022Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundThe echinoderm microtubule-associated protein-like-4 anaplastic lymphoma kinase (EML4-ALK) fusion gene was identified in a subset of non-small cell lung cancer (NSCLC) patients. They responded positively to ALK inhibitors. This study aimed to characterize the mechanisms triggered by EML4-ALK to induce NSCLC transformation.
methodsHEK293 and NIH3T3 cells were transfected with EML4-ALK variant 3 or pcDNA3.1-NC. H2228 cells were transfected with siRNA-EML4-ALK or siRNA-NC. Cell viability and proliferation were measured by the CCK-8 and EdU methods, respectively. Flow cytometry revealed apoptosis. Gene expression profiles were generated from a signaling pathway screen in EML4-ALK-regulated lung cancer cells and verified by qPCR and Western blotting. The co-immunoprecipitation and immunohistochemistry/ immunofluorescence determined the interaction and colocalization of JAK2-STAT pathway components with EML4-ALK.
resultsMicroarray identified several genes involved in the JAK2-STAT pathway. JAK2 and STAT6 were constitutively phosphorylated in H2228 cells. EML4-ALK silencing downregulated phosphorylation of STAT6. Expression of EML4-ALK in HEK293 and NIH3T3 cells activated JAK2, STAT1, STAT3, STAT5, and STAT6. In EML4-ALK-transfected HEK293 cells and EML4-ALK-positive H2228 cells, activated STAT6 and JAK2 colocalized with ALK. STAT3 and STAT6 were phosphorylated and translocated to the nucleus of H2228 cells following IL4 or IL6 treatment. Apoptosis increased, while cell proliferation and DNA replication decreased in H2228 cells following EML4-ALK knockdown. In contrast, HEK293 cell viability increased following EML4-ALK overexpression, while H2228 cell viability significantly decreased after treatment with ALK or JAK-STAT pathway inhibitors.
conclusionsOur data suggest that the aberrant expression of EML4-ALK leads to JAK2-STAT signaling pathway activation, which is essential for the development of non-small cell lung cancer.
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