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Autocrine HGF/c-Met signaling pathway confers aggressiveness in lymph node adult T-cell leukemia/lymphoma

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.

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Fig. 1: Expression of HGF in ATL cell lines and clinical samples.
Fig. 2: HGF promotes ATL cell proliferation and invasion.
Fig. 3: Effects of HGF/c-Met signaling and its downstream pathway on ATL cell growth.
Fig. 4: Regulation of HGF expression by epigenetic mechanisms.
Fig. 5: Serum HGF expression in clinical samples.

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Acknowledgements

This study was performed as research program with a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (25290048, YK; 19K16752, HT) and the National Cancer Center Research and Development Fund (29-A-3, SI).

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Conception and design: HT, YK; development of methodology: HT, KS, MS, KK, AM, AI, YK; acquisition of data: HT, KS, MS, KK, SM, AM, AI, MR, SK, HK, HI, TI, SI, YK; analysis and interpretation of data: HT, KS, MS, AM, AI, TI, HI, SI, YK; writing of the paper: HT, YK; administrative, technical, or material support: TI, HI, SI, YK.

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Correspondence to Yutaka Kondo.

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Totani, H., Shinjo, K., Suzuki, M. et al. Autocrine HGF/c-Met signaling pathway confers aggressiveness in lymph node adult T-cell leukemia/lymphoma. Oncogene 39, 5782–5794 (2020). https://doi.org/10.1038/s41388-020-01393-x

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