Suppression of hyaluronan synthesis attenuates the tumorigenicity of low-grade chondrosarcoma
Suppression of hyaluronan synthesis attenuates the tumorigenicity of low-grade chondrosarcoma
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抑制透明质酸合成可减弱低度软骨肉瘤的致瘤性
DOI：
10.1002/jor.23794
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Ishiguro Naoki
中科院分区：
文献类型：
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作者：
Hamada Shunsuke;Nishida Yoshihiro;Zhuo Lisheng;Shinomura Tamayuki;Ikuta Kunihiro;Arai Eisuke;Koike Hiroshi;Kimata Koji;Ushida Takahiro;Ishiguro Naoki
透明质酸（HA）在恶性肿瘤的致瘤性中起重要作用。软骨肉瘤，特别是当低级别时，其特征在于形成含有丰富HA的细胞外基质（ECM），并且其药物/辐射抗性已成为临床相关问题。本研究旨在评价HA合成抑制剂4-甲基伞形酮（MU）对软骨肉瘤ECM形成的影响以及抗肿瘤作用。我们研究了MU对大鼠软骨肉瘤（RCS）细胞与I级组织学恶性肿瘤在体外和体内移植模型的影响。HA结合蛋白（HABP）在RCS细胞上和周围的治疗有效地减少与MU的治疗。MU在1.0 mM剂量下显著抑制ECM形成。MU在24 h时显著降低细胞增殖。MU以剂量依赖性方式抑制细胞运动和侵袭。没有观察到Has 1 −3的mRNA表达的显著变化。此外，MU在体内抑制移植肿瘤的生长。在组织学上，对照肿瘤的软骨肉瘤细胞显示细胞聚集结构。MU治疗组的HABP显著降低。这些结果表明，MU通过抑制HA积累和ECM形成对低度软骨肉瘤表现出抗肿瘤作用。MU是一种获批的胆汁治疗药物，可能是一种新的软骨肉瘤标签外药物。© 2017骨科研究学会。出版社：Wiley Periodicals，Inc. J Orthop Res 36：1573-1580，2018。
Hyaluronan (HA) has been shown to play crucial roles in the tumorigenicity of malignant tumors. Chondrosarcoma, particularly when low‐grade, is characterized by the formation of an extracellular matrix (ECM) containing abundant HA, and its drug/radiation resistance has become a clinically relevant problem. This study aimed to evaluate the effects of an HA synthesis inhibitor, 4‐methylumbelliferone (MU), on ECM formation as well as antitumor effects in chondrosarcoma. We investigated the effects of MU on rat chondrosarcoma (RCS) cells with a grade I histological malignancy in vitro and in vivo grafted model. HA binding protein (HABP) stainability on and around the RCS cells was effectively reduced with treatment of MU. ECM formation was markedly suppressed by MU at a dose of 1.0 mM. Cell proliferation was significantly reduced by MU at 24 h. Cell motility and invasion were suppressed in a dose‐dependent manner by MU. No significant changes in mRNA expression of Has1−3 were observed. Furthermore, MU inhibited the growth of grafted tumors in vivo. Histologically, chondrosarcoma cells of control tumors showed a cell‐clustering structure. HABP stainability was markedly decreased in the MU‐treated group. These results suggest that MU exhibits antitumor effects on low‐grade chondrosarcoma, via inhibition of HA accumulation and ECM formation. MU, which is an approved drug in bile therapy, could be a new off‐label medication for chondrosarcomas. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1573–1580, 2018.