Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, 150001,, Heilongjiang Province, China.
Key Colleges and Universities Laboratory of Neurosurgery in Heilongjiang Province, Harbin, 150001,, Heilongjiang Province, China.
Cell Death Dis. 2021 May 13;12(5):486. doi: 10.1038/s41419-021-03747-z.
The tumor microenvironment plays an important role in tumor progression. Hyaluronic acid (HA), an important component of the extracellular matrix in the tumor microenvironment, abnormally accumulates in a variety of tumors. However, the role of abnormal HA accumulation in glioma remains unclear. The present study indicated that HA, hyaluronic acid synthase 3 (HAS3), and a receptor of HA named CD44 were expressed at high levels in human glioma tissues and negatively correlated with the prognosis of patients with glioma. Silencing HAS3 expression or blocking CD44 inhibited glioma cell proliferation in vitro and in vivo. The underlying mechanism was attributed to the inhibition of autophagy flux and maintaining glioma cell cycle arrest in G1 phase. More importantly, 4-methylumbelliferone (4-MU), a small competitive inhibitor of Uridine diphosphate (UDP) with the ability to penetrate the blood-brain barrier (BBB), also inhibited glioma cell proliferation in vitro and in vivo. Thus, approaches that interfere with HA metabolism by altering the expression of HAS3 and CD44 and the administration of 4-MU potentially represent effective strategies for glioma treatment.
肿瘤微环境在肿瘤进展中起着重要作用。透明质酸（HA）是肿瘤微环境细胞外基质的重要组成部分，在多种肿瘤中异常积聚。然而，异常 HA 积聚在神经胶质瘤中的作用尚不清楚。本研究表明，HA、透明质酸合酶 3（HAS3）和 HA 的一种受体 CD44 在人神经胶质瘤组织中表达水平较高，与神经胶质瘤患者的预后呈负相关。沉默 HAS3 表达或阻断 CD44 抑制了体外和体内神经胶质瘤细胞的增殖。其潜在机制归因于自噬流的抑制和维持神经胶质瘤细胞周期停滞在 G1 期。更重要的是，4-甲基伞形酮（4-MU）是一种具有穿透血脑屏障（BBB）能力的 UDP 小分子竞争抑制剂，也能抑制体外和体内神经胶质瘤细胞的增殖。因此，通过改变 HAS3 和 CD44 的表达以及 4-MU 的给药来干扰 HA 代谢的方法可能代表治疗神经胶质瘤的有效策略。
