Tsuru A, Setoguchi T, Matsunoshita Y, Nagao-Kitamoto H, Nagano S, Yokouchi M, Maeda S, Ishidou Y, Yamamoto T, Komiya S
Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
The Near-Future Locomotor Organ Medicine Creation Course (Kusunoki Kai), Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
Br J Cancer. 2015 Mar 31;112(7):1232-40. doi: 10.1038/bjc.2015.84.
Activation of the Notch pathway has been reported in various types of cancers. However, the role of the hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) in osteosarcoma is unknown. We examined the function of HEY1 in osteosarcoma.
Expression of HEY1 was studied in human osteosarcoma. The effects of HEY1 in osteosarcoma were evaluated in vitro and in a xenograft model. Moreover, we examined the function of matrix metallopeptidase 9 (MMP9) as a downstream effector of HEY1.
HEY1 was upregulated in human osteosarcoma. Knockdown of HEY1 inhibited the invasion of osteosarcoma cell lines. In contrast, the forced expression of HEY1 increased the invasion of mesenchymal stem cell. In addition, lung metastases were significantly inhibited by the knockdown of HEY1. We found that MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells. Knockdown of HEY1 decreased the expression of MMP9. Addition of MMP9 rescued the invasion of osteosarcoma cells that had been rendered less invasive by knockdown of HEY1 expression.
Our findings suggested that HEY1 augmented the metastasis of osteosarcoma via upregulation of MMP9 expression. Therefore, inhibition of HEY1 may be a novel therapeutic strategy for preventing osteosarcoma metastasis.
已有报道称Notch通路在多种癌症类型中被激活。然而，毛状/分裂增强子相关YRPW基序蛋白1（HEY1）在骨肉瘤中的作用尚不清楚。我们研究了HEY1在骨肉瘤中的功能。
研究了HEY1在人骨肉瘤中的表达。在体外和异种移植模型中评估了HEY1对骨肉瘤的影响。此外，我们研究了基质金属蛋白酶9（MMP9）作为HEY1下游效应分子的功能。
HEY1在人骨肉瘤中上调。敲低HEY1可抑制骨肉瘤细胞系的侵袭。相反，HEY1的强制表达增加了间充质干细胞的侵袭。此外，敲低HEY1可显著抑制肺转移。我们发现MMP9是HEY1的下游效应分子，可促进骨肉瘤细胞的侵袭。敲低HEY1可降低MMP9的表达。添加MMP9可挽救因敲低HEY1表达而侵袭性降低的骨肉瘤细胞的侵袭能力。
我们的研究结果表明，HEY1通过上调MMP9表达增强了骨肉瘤的转移。因此，抑制HEY1可能是预防骨肉瘤转移的一种新的治疗策略。
Zotero 插件