Vo Thuy-Trang T, Tran Quangdon, Hong Youngeun, Lee Hyunji, Cho Hyeonjeong, Kim Minhee, Park Sungjin, Kim Chaeyeong, Bayarmunkh Choinyam, Boldbaatar Damdindorj, Kwon So Hee, Park Jisoo, Kim Seon-Hwan, Park Jongsun
Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, 35015 Republic of Korea.
Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015 Republic of Korea.
Toxicol Res. 2023 Jun 14;39(4):669-679. doi: 10.1007/s43188-023-00195-z. eCollection 2023 Oct.
Glioblastoma (GBM) is the most aggressive type of central nervous system tumor. Molecular targeting may be important when developing efficient GBM treatment strategies. Sequencing of GBMs revealed that the receptor tyrosine kinase (RTK)/RAS/phosphatidylinositol-3-kinase pathway was altered in 88% of samples. Interestingly, AXL, a member of RTK, was proposed as a promising target in glioma therapy. However, the molecular mechanism of AXL modulation of GBM genesis and proliferation is still unclear. In this study, we investigated the expression and localization of hypoxia-inducible factor-1 alpha (HIF-1α) by AXL in GBM. Both AXL mRNA and protein are overexpressed in GBM. Short-interfering RNA knockdown of AXL in U251-MG cells reduced viability and migration. However, serum withdrawal reduced AXL expression, abolishing the effect on viability. AXL is also involved in hypoxia regulation. In hypoxic conditions, the reduction of AXL decreased the level and nuclear localization of HIF-1α. The co-expression of HIF-1α and AXL was found in human GBM samples but not normal tissue. This finding suggests a mechanism for GBM proliferation and indicates that targeting AXL may be a potential GBM therapeutic.
The online version contains supplementary material available at 10.1007/s43188-023-00195-z.
胶质母细胞瘤（GBM）是中枢神经系统中最具侵袭性的肿瘤类型。在制定有效的GBM治疗策略时，分子靶向可能很重要。对GBM的测序显示，88%的样本中受体酪氨酸激酶（RTK）/RAS/磷脂酰肌醇-3-激酶途径发生了改变。有趣的是，RTK成员AXL被认为是胶质瘤治疗中有前景的靶点。然而，AXL调节GBM发生和增殖的分子机制仍不清楚。在本研究中，我们研究了AXL在GBM中对缺氧诱导因子-1α（HIF-1α）表达和定位的影响。AXL的mRNA和蛋白在GBM中均过表达。在U251-MG细胞中用短干扰RNA敲低AXL可降低细胞活力和迁移能力。然而，血清饥饿会降低AXL表达，消除其对细胞活力的影响。AXL也参与缺氧调节。在缺氧条件下，AXL的减少会降低HIF-1α的水平和核定位。在人类GBM样本中发现了HIF-1α和AXL的共表达，但在正常组织中未发现。这一发现提示了GBM增殖的一种机制，并表明靶向AXL可能是一种潜在的GBM治疗方法。
在线版本包含可在10.1007/s43188-023-00195-z获取的补充材料。
