Translocation of heparanase into nucleus results in cell differentiation
Translocation of heparanase into nucleus results in cell differentiation
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DOI：
10.1111/j.1349-7006.2007.00420.x
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发表时间：
2007-04-01
期刊：
影响因子：
5.7
通讯作者：
Tanaka, Noriaki
中科院分区：
文献类型：
--
作者：
Nobuhisa, Tetsuji;Naomoto, Yoshio;Tanaka, Noriaki
我们最近报道，乙酰肝素酶是一种细胞外基质降解酶，在癌症的发展中起着关键作用，它不仅位于细胞质中，而且位于细胞核中。在这里，我们发现乙酰肝素酶的核转位是细胞分化的关键步骤。我们应用12-0-十四酰佛波醇-13-乙酸酯(TPA)体外诱导HL-60细胞分化的模型，用免疫组织化学方法观察了肝素酶的核转位。在这个系统中，肝素酶的核转位被热休克蛋白90(HSP90)的抑制剂取消，这表明HSP90参与了肝素酶的转位。我们进一步证实了活性形式的乙酰肝素酶的过表达诱导了HL-60细胞的分化，尽管催化阴性形式的乙酰肝素酶不能。因此，我们推测具有酶活性的乙酰肝素酶的核转位可能与细胞分化有关。我们的结果表明，乙酰肝素酶在细胞分化中的新功能将为早幼粒细胞白血病和其他类型癌症的治疗提供一种潜在的新策略。
We recently reported that heparanase, one of the extracellular matrix-degrading enzymes, which plays a critical role in cancer progression, is located not only in the cytoplasm but also in the nucleus. Here we identified nuclear translocation of heparanase as a key step in cell differentiation. We applied an in vitro differentiation model of HL-60 cells with 12-0-tetradecanoylphorbol-13-acetate (TPA), in which nuclear translocation of heparanase was observed using immunohistochemical analysis. In this system, nuclear translocation of heparanase was abolished by inhibitors of heat shock protein 90 (HSP90), suggesting the involvement of HSP90 in translocation of heparanase. We further confirmed that overexpression of active form of heparanase induced differentiation of HL-60 cells, although the catalytic negative form of heparanase did not. Therefore we speculate that nuclear translocation of enzymatically active heparanase may be involved in cellular differentiation. Our results suggest that a novel function of heparanase upon cell differentiation would raise a potential new strategy for cancer therapy of promyeloid leukemia and other types of cancer.