Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Department of Rehabilitation Medicine, Nagoya University Hospital, Nagoya, Aichi, Japan.
J Orthop Res. 2020 Sep;38(9):1942-1951. doi: 10.1002/jor.24629. Epub 2020 Feb 27.
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 a novel hyaluronidase, KIAA1199, on ECM formation as well as antitumor effects on chondrosarcoma. To clarify the roles of KIAA1199 in chondrosarcoma, mouse KIAA1199 was stably transfected to Swarm rat chondrosarcoma (RCS) cells (histologically grade 1). We investigated the effects of KIAA1199 on RCS cells in vitro and an autografted model in vivo. HA binding protein (HABP) stainability and ECM formation in KIAA1199-RCS was markedly suppressed compared with that of control cells. No significant changes in messenger RNA expression of Has1, Has2, Has3, Hyal1, or Hyal2 were observed. KIAA1199 expression did not affect proliferation or apoptosis but inhibited migration and invasion of RCS cells. In contrast, the expression of KIAA1199 significantly inhibited the growth of grafted tumors and suppressed the stainability of alcian blue in tumor tissues. Although there was no direct inhibitory effect on proliferation in vitro, induction of KIAA1199 showed the antitumor effects in grafted tumor growth in vivo possibly due to changes in the tumor microenvironment such as inhibition of ECM formation. Forced expression of KIAA1199 exhibits antitumor effects on low-grade chondrosarcoma, which has chemo- and radio-therapy resistant features. Together, KIAA1199 could be a novel promising therapeutic tool for low-grade chondrosarcoma, mediated by the degradation of HA.
透明质酸（HA）已被证明在恶性肿瘤的致瘤性中发挥关键作用。软骨肉瘤，尤其是低度恶性软骨肉瘤，其特征是形成富含 HA 的细胞外基质（ECM），其耐药性已成为一个临床相关问题。本研究旨在评估一种新型透明质酸酶 KIAA1199 对软骨肉瘤 ECM 形成和抗肿瘤作用的影响。为了阐明 KIAA1199 在软骨肉瘤中的作用，我们将小鼠 KIAA1199 稳定转染至 Swarm 大鼠软骨肉瘤（RCS）细胞（组织学分级 1）。我们研究了 KIAA1199 对 RCS 细胞的体外和自体移植模型的影响。与对照细胞相比，KIAA1199-RCS 中的 HA 结合蛋白（HABP）染色性和 ECM 形成明显受到抑制。Has1、Has2、Has3、Hyal1 或 Hyal2 的信使 RNA 表达没有明显变化。KIAA1199 的表达并不影响增殖或凋亡，但抑制了 RCS 细胞的迁移和侵袭。相反，KIAA1199 的表达显著抑制了移植瘤的生长，并抑制了肿瘤组织中阿利新蓝的染色性。虽然体外没有直接的增殖抑制作用，但 KIAA1199 的诱导在体内移植瘤生长中表现出抗肿瘤作用，可能是由于肿瘤微环境的变化，如 ECM 形成的抑制。强制表达 KIAA1199 对具有化疗和放疗耐药特征的低度软骨肉瘤表现出抗肿瘤作用。总之，KIAA1199 可能成为一种新型的有前途的治疗低度软骨肉瘤的工具，其作用机制可能是通过降解 HA 介导的。
