title: Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia-induced epithelial-mesenchymal transition in non-small cell lung cancer.
abstract: 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.
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Fariz
authors.initials: F
authors.lastname: Nurwidya
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan. Electronic address: fumiyuki@dol.hi-ho.ne.jp.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Takahashi
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Kobayashi
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Murakami
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Minakata
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nara
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Yagishita
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hario
authors.initials: H
authors.lastname: Baskoro
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Moulid
authors.initials: M
authors.lastname: Hidayat
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Shimada
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005353:Fibronectins / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014746:Vimentin / Q000378:metabolism; D014945:Wound Healing
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D005353:Fibronectins; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D014746:Vimentin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D010100:Oxygen
keywords: EMT; IGF1R signaling; NSCLC