Autocrine HGF/c-Met signaling pathway confers aggressiveness in lymph node adult T-cell leukemia/lymphoma
Autocrine HGF/c-Met signaling pathway confers aggressiveness in lymph node adult T-cell leukemia/lymphoma
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DOI：
10.1038/s41388-020-01393-x
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发表时间：
2020-08
期刊：
影响因子：
8
通讯作者：
H. Totani;Keiko Shinjo;Miho Suzuki;Keisuke Katsushima;S. Mase;A. Masaki;A. Ito;M. Ri;S. Kusumoto;H. Komatsu;T. Ishida;H. Inagaki;S. Iida;Y. Kondo
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文献类型：
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作者：
H. Totani;Keiko Shinjo;Miho Suzuki;Keisuke Katsushima;S. Mase;A. Masaki;A. Ito;M. Ri;S. Kusumoto;H. Komatsu;T. Ishida;H. Inagaki;S. Iida;Y. Kondo
成人T细胞白血病/淋巴瘤（ATL）是一种侵袭性T细胞肿瘤。虽然外周血中的ATL细胞（PB-ATL）对抗CC趋化因子受体4治疗敏感，但非PB-ATL（包括淋巴结ATL（LN-ATL））更具侵袭性和抗性。我们研究了与PB-ATL相比，允许非PB-ATL增殖和侵袭的特征性细胞因子和生长因子。蛋白阵列分析显示，与PB-ATL相比，非PB-ATL中肝细胞生长因子（HGF）和C-C基序趋化因子2（CCL 2）显著上调。HGF膜受体c-Met在PB-ATL和非PB-ATL细胞系中表达，但CCL 2受体CCR 2不表达。临床ATL的免疫组化分析显示，淋巴结、咽、骨髓和扁桃体中HGF表达较高。HGF/c-Met信号通路在非PB-ATL中下游活跃。通过siRNA或化学抑制剂下调HGF/c-Met可降低体外和体内非PB-ATL的增殖和侵袭。用溴结构域和末端外基序抑制剂处理抑制HGF表达，并降低组蛋白H3赖氨酸27乙酰化（H3 K27 Ac）和含溴结构域蛋白4（BRD 4）结合启动子和增强子区域的水平，抑制非PB-ATL细胞生长。我们的数据表明H3 K27 Ac/BRD 4表观遗传学调节ATL中的HGF/c-MET通路;靶向该通路可以改善侵袭性非PB-ATL的治疗。
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.