HYBID derived from tumor cells and tumor-associated macrophages contribute to the glioblastoma growth
HYBID derived from tumor cells and tumor-associated macrophages contribute to the glioblastoma growth
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DOI：
10.1016/j.brainres.2021.147490
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发表时间：
2021-04
期刊：
影响因子：
2.9
通讯作者：
Shohei Tsuji;Shinsuke Nakamura;Tetsuya Yamada;S. de Vega;Y. Okada;S. Inoue;M. Shimazawa;H. Hara
中科院分区：
文献类型：
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作者：
Shohei Tsuji;Shinsuke Nakamura;Tetsuya Yamada;S. de Vega;Y. Okada;S. Inoue;M. Shimazawa;H. Hara
胶质母细胞瘤是与不良预后和结果相关的最恶性的脑肿瘤，因此迫切需要开发用于胶质母细胞瘤的新治疗。在这项研究中，我们专注于透明质酸结合蛋白（HYBID，称为CEMIP/KIAA 1199），一种参与软骨细胞和滑膜细胞中透明质酸解聚的蛋白质。我们以前报道过杂交缺陷（KO）小鼠表现出大脑中透明质酸的积累和记忆障碍。为了阐明HYBID在胶质母细胞瘤发病机制中的作用，我们使用siRNA敲除人胶质母细胞瘤细胞中的HYBID，并在HybidKO小鼠中建立了小鼠原位异种移植模型。胶质母细胞瘤细胞中HYBID的下调导致细胞增殖和迁移的抑制，并增加细胞死亡。与野生型小鼠相比，植入小鼠脑中的胶质母细胞瘤细胞的生长在HybidKO小鼠中受到抑制。有趣的是，在HybidKO小鼠中，胶质母细胞瘤组织中的巨噬细胞浸润减少。利用来自HybidKO小鼠的腹腔巨噬细胞和胶质瘤细胞上清液，我们研究了HYBID在肿瘤环境中巨噬细胞中的作用。我们发现HYBID有助于巨噬细胞迁移和促肿瘤因子的释放。此外，我们通过生物信息学方法揭示了HYBID可能是胶质瘤患者预后不良的因素。我们的研究提供的数据支持胶质母细胞瘤细胞和肿瘤相关巨噬细胞表达的HYBID可能有助于胶质母细胞瘤的进展，并表明HYBID可能是一个潜在的治疗靶点，专注于胶质母细胞瘤的肿瘤微环境。
Glioblastoma is the most malignant tumor of the brain associated with poor prognosis and outcome, and hence there is an urgent need to develop novel treatments for glioblastoma. In this study, we focused on hyaluronan binding protein (HYBID, as known as CEMIP/KIAA1199), a protein involved in hyaluronan depolymerization in chondrocytes and synoviocytes. We previously reported thatHybid-deficient (KO) mice show accumulation of hyaluronan in the brain, and memory impairment. To elucidate the role of HYBID in glioblastoma pathogenesis, we knocked down HYBID in human glioblastoma cells using siRNAs and developed a murine orthotopic xenograft model in theHybidKO mice. Downregulation of HYBID in glioblastoma cells resulted in inhibition of cell proliferation and migration, and increased cell death. The growth of glioblastoma cells implanted in the mouse brain was suppressed inHybidKO mice compared to that in the wild-type mice. Interestingly, infiltration of macrophages in the glioblastoma tissue was decreased inHybidKO mice. Using intraperitoneal macrophages derived fromHybidKO mice and glioma cell supernatants, we examined the role of HYBID in macrophages in the tumor environment. We showed that HYBID contributes to macrophage migration and the release of pro-tumor factors. Moreover, we revealed that HYBID can be a poor prognostic factor in glioma patients by bioinformatics approaches. Our study provides data to support that HYBID expressed by both glioblastoma cells and tumor-associated macrophages may contribute to glioblastoma progression and suggests that HYBID may be a potential target for therapy that focuses on the tumor microenvironment of glioblastoma.