RRC ID 62979
Author Totani H, Shinjo K, Suzuki M, Katsushima K, Mase S, Masaki A, Ito A, Ri M, Kusumoto S, Komatsu H, Ishida T, Inagaki H, Iida S, Kondo Y.
Title Autocrine HGF/c-Met signaling pathway confers aggressiveness in lymph node adult T-cell leukemia/lymphoma.
Journal Oncogene
Abstract 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.
Volume 39(35)
Pages 5782-5794
Published 2020-8-1
DOI 10.1038/s41388-020-01393-x
PII 10.1038/s41388-020-01393-x
PMID 32747750
MeSH Animals Cell Line, Tumor Hepatocyte Growth Factor / metabolism* Humans Leukemia-Lymphoma, Adult T-Cell / genetics* Lymph Nodes / pathology* Mice Signal Transduction
IF 7.971
Human and Animal Cells RAW 264(RCB0535)