Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia-induced epithelial–mesenchymal transition in non-small cell lung cancer
| Autor: | Naoko Shimada, Takeshi Nara, Kazuhisa Takahashi, Fariz Nurwidya, Motoyasu Kato, Muneaki Hashimoto, Shigehiro Yagishita, Isao Kobayashi, Akiko Murakami, Kunihiko Minakata, Moulid Hidayat, Fumiyuki Takahashi, Hario Baskoro |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Epithelial-Mesenchymal Transition
Lung Neoplasms medicine.medical_treatment Cell Biophysics IGFBP3 Vimentin Biology Biochemistry Receptor IGF Type 1 Metastasis Antigens CD Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Humans Epithelial–mesenchymal transition Insulin-Like Growth Factor I Neoplasm Metastasis Molecular Biology Insulin-like growth factor 1 receptor Wound Healing Gene Expression Profiling Growth factor Cell Biology Cadherins medicine.disease Molecular biology Cell Hypoxia Fibronectins Gene Expression Regulation Neoplastic Oxygen body regions Insulin-Like Growth Factor Binding Protein 3 Phenotype medicine.anatomical_structure Disease Progression Cancer research biology.protein Signal Transduction Transforming growth factor |
| Zdroj: | Biochemical and Biophysical Research Communications. 455:332-338 |
| ISSN: | 0006-291X |
| Popis: | Insulin-like growth factor 1 receptor (IGF1R) is expressed in many types of solid tumors including non-small cell lung cancer (NSCLC), and enhanced activation of IGF1R is thought to reflect cancer progression. Epithelial-mesenchymal transition (EMT) has been established as one of the mechanisms responsible for cancer progression and metastasis, and microenvironment conditions, such as hypoxia, have been shown to induce EMT. The purposes of this study were to address the role of IGF1R activation in hypoxia-induced EMT in NSCLC and to determine whether inhibition of IGF1R might reverse hypoxia-induced EMT. Human NSCLC cell lines A549 and HCC2935 were exposed to hypoxia to investigate the expression of EMT-related genes and phenotypes. Gene expression analysis was performed by quantitative real-time PCR and cell phenotypes were studied by morphology assessment, scratch wound assay, and immunofluorescence. Hypoxia-exposed cells exhibited a spindle-shaped morphology with increased cell motility reminiscent of EMT, and demonstrated the loss of E-cadherin and increased expression of fibronectin and vimentin. Hypoxia also led to increased expression of IGF1, IGF binding protein-3 (IGFBP3), and IGF1R, but not transforming growth factor β1 (TGFβ1). Inhibition of hypoxia-inducible factor 1α (HIF1α) with YC-1 abrogated activation of IGF1R, and reduced IGF1 and IGFBP3 expression in hypoxic cells. Furthermore, inhibition of IGF1R using AEW541 in hypoxic condition restored E-cadherin expression, and reduced expression of fibronectin and vimentin. Finally, IGF1 stimulation of normoxic cells induced EMT. Our findings indicated that hypoxia induced EMT in NSCLC cells through activation of IGF1R, and that IGF1R inhibition reversed these phenomena. These results suggest a potential role for targeting IGF1R in the prevention of hypoxia-induced cancer progression and metastasis mediated by EMT. |
| Databáze: | OpenAIRE |
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