HMGB1 as an autocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration
HMGB1 as an autocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration
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DOI：
10.1007/s11060-007-9488-y
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发表时间：
2008-03-01
影响因子：
3.9
通讯作者：
Riboni, Laura
中科院分区：
文献类型：
--
作者：
Bassi, Rosaria;Giussani, Paola;Riboni, Laura
HMGB1（高迁移率族盒 1 蛋白）是一种核蛋白，主要通过 RAGE（晚期糖基化终产物的受体）充当细胞外炎症、增殖和迁移的触发因素； HMGB1-RAGE 相互作用被发现在许多癌症中很重要。我们研究了 HMGB1 是否是人胶质瘤细胞中的自分泌因子。蛋白质印迹显示人恶性胶质瘤细胞系中 HMGB1 和 RAGE 表达。 HMGB1 诱导细胞增殖呈剂量依赖性增加，这被发现是 RAGE 介导的并涉及 MAPK/ERK 通路。此外，在受伤模型中，它诱导细胞迁移显着增加，Rac1 的 RAGE 依赖性激活对于赋予肿瘤细胞运动表型至关重要。用抗有丝分裂剂阻断 DNA 复制并没有减少迁移距离的事实表明增殖和迁移效应的独立性。我们还发现，胶质瘤细胞主要在细胞核中含有 HMGB1，并且不能组成型或受刺激时分泌。然而，坏死的神经胶质瘤细胞在从细胞核转移到细胞质后可以释放 HMGB1。这些发现为支持人胶质母细胞瘤细胞中存在HMGB1/RAGE信号通路提供了第一个证据，并表明HMGB1可能通过作为能够促进肿瘤细胞生长和迁移的自分泌因子，在胶质瘤坏死和恶性之间的关系中发挥重要作用。
HMGB1 (high mobility group box 1 protein) is a nuclear protein that can also act as an extracellular trigger of inflammation, proliferation and migration, mainly through RAGE (the receptor for advanced glycation end products); HMGB1-RAGE interactions have been found to be important in a number of cancers. We investigated whether HMGB1 is an autocrine factor in human glioma cells. Western blots showed HMGB1 and RAGE expression in human malignant glioma cell lines. HMGB1 induced a dose-dependent increase in cell proliferation, which was found to be RAGE-mediated and involved the MAPK/ERK pathway. Moreover, in a wounding model, it induced a significant increase in cell migration, and RAGE-dependent activation of Rac1 was crucial in giving the tumour cells a motile phenotype. The fact that blocking DNA replication with anti-mitotic agents did not reduce the distance migrated suggests the independence of the proliferative and migratory effects. We also found that glioma cells contain HMGB1 predominantly in the nucleus, and cannot secrete it constitutively or upon stimulation; however, necrotic glioma cells can release HMGB1 after it has translocated from the nucleus to cytosol. These findings provide the first evidence supporting the existence of HMGB1/RAGE signalling pathways in human glioblastoma cells, and suggest that HMGB1 may play an important role in the relationship between necrosis and malignancy in glioma tumours by acting as an autocrine factor that is capable of promoting the growth and migration of tumour cells.