2024-03-28T08:59:33Z
https://nagoya.repo.nii.ac.jp/oai
oai:nagoya.repo.nii.ac.jp:00031053
2023-01-16T04:43:31Z
499:500:501
Autocrine HGF/c-Met signaling pathway confers aggressiveness in lymph node adult T-cell leukemia/lymphoma
Totani, Haruhito
Shinjo, Keiko
Suzuki, Miho
Katsushima, Keisuke
Mase, Shoko
Masaki, Ayako
Ito, Asahi
Ri, Masaki
Kusumoto, Shigeru
Komatsu, Hirokazu
Ishida, Takashi
Inagaki, Hiroshi
Iida, Shinsuke
Kondo, Yutaka
open access
Cytokines
Histone post-translational modifications
Leukaemia
Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasm. While ATL cells in peripheral blood (PB-ATL) are sensitive to anti-CC chemokine receptor 4 treatment, non–PB-ATLs, including lymph node ATLs (LN-ATLs), are more aggressive and resistant. We examined characteristic cytokines and growth factors that allow non–PB-ATLs to proliferate and invade compared with PB-ATLs. Protein array analysis revealed hepatocyte growth factor (HGF) and C-C motif chemokine 2 (CCL2) were significantly upregulated in non–PB-ATLs compared with PB-ATLs. The HGF membrane receptor, c-Met, was expressed in PB-ATL and non–PB-ATL cell lines, but CCR2, a CCL2 receptor, was not. Immunohistochemical analysis in clinical ATLs revealed high HGF expression in LNs, pharynx, bone marrow, and tonsils. The HGF/c-Met signaling pathway was active downstream in non–PB-ATLs. Downregulation of HGF/c-Met by siRNA or chemical inhibitors decreased in vitro and in vivo proliferation and invasion by non–PB-ATLs. Treatment with bromodomain and extra-terminal motif inhibitor suppressed HGF expression and decreased levels of histone H3 lysine 27 acetylation (H3K27Ac) and bromodomain-containing protein 4 (BRD4) binding promoter and enhancer regions, suppressing non–PB-ATL cellular growth. Our data indicate H3K27Ac/BRD4 epigenetics regulates the HGF/c-MET pathway in ATLs; targeting this pathway may improve treatment of aggressive non–PB-ATLs.
ファイル公開:2021/02/27
Springer Nature
2020-02-27
eng
journal article
AM
http://hdl.handle.net/2237/00033234
https://nagoya.repo.nii.ac.jp/records/31053
https://doi.org/10.1038/s41388-020-01393-x
0950-9232
Oncogene
39
35
5782
5794
https://nagoya.repo.nii.ac.jp/record/31053/files/NAGOYARepository_Kondo_Yutaka.pdf
application/pdf
1.8 MB
2021-02-27