Department of Neurobiology and Anatomy, Xuzhou Key Laboratory of Neurobiology, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
Mol Neurobiol. 2022 Oct;59(10):6321-6340. doi: 10.1007/s12035-022-02978-1. Epub 2022 Aug 4.
Glial cell-line derived neurotrophic factor (GDNF) is a powerful astroglioma (AG) proliferation and migration factor that is highly expressed in AG cells derived from astrocytes. However, it is still unclear whether high levels of GDNF promote AG occurrence or if they are secondary to AG formation. We previously reported that high concentrations of GDNF (200 and 500 ng/mL) can inhibit DNA damage-induced rat primary astrocytes (RA) apoptosis, suggesting that high concentrations of GDNF may be involved in the malignant transformation of astrocytes to AG cells. Here we show that 200 ng/mL GDNF significantly increased the proliferation and migration ability of RA cells and human primary astrocytes (HA). This treatment also induced RA cells to highly express Pgf, Itgb2, Ibsp, Loxl2, Lif, Cxcl10, Serpine1, and other genes that enhance AG proliferation and migration. LOXL2 is an important AG occurrence and development promotion factor and was highly expressed in AG tissues and cells. High concentrations of GDNF promote LOXL2 expression and secretion in RA cells through GDNF family receptor alpha-1(GFRα1)/rearranged during transfection proto-oncogene (RET)/mitogen-activated protein kinase (MAPK)/phosphorylated cyclic AMP response element binding protein (pCREB) signaling. GDNF-induced LOXL2 significantly promotes RA and HA cell proliferation and migration, and increases the expression of Ccl2, Gbp5, MMP11, TNN, and other genes that regulate the extracellular microenvironment in RA cells. Our results demonstrate that high concentrations of GDNF activate LOXL2 expression and secretion via the GFRα1/RET/MAPK/pCREB signal axis, which leads to remodeling of the astrocyte extracellular microenvironment through molecules such as Ccl2, Gbp5, MMP11, TNN. This ultimately results in abnormal astrocyte proliferation and migration. Collectively, these findings suggest that high GDNF concentrations may promote the malignant transformation of astrocytes to AG cells.
胶质细胞源性神经营养因子（GDNF）是一种强大的神经胶质瘤（AG）增殖和迁移因子，在星形胶质细胞衍生的 AG 细胞中高度表达。然而，目前尚不清楚高浓度的 GDNF 是否促进 AG 的发生，或者它们是否是 AG 形成的继发事件。我们之前报道过高浓度的 GDNF（200 和 500ng/ml）可以抑制 DNA 损伤诱导的大鼠原代星形胶质细胞（RA）凋亡，这表明高浓度的 GDNF 可能参与了星形胶质细胞向 AG 细胞的恶性转化。在这里，我们发现 200ng/ml 的 GDNF 可显著增加 RA 细胞和人原代星形胶质细胞（HA）的增殖和迁移能力。这种处理还诱导 RA 细胞高度表达 Pgf、Itgb2、Ibsp、Loxl2、Lif、Cxcl10、Serpine1 和其他增强 AG 增殖和迁移的基因。LOXL2 是 AG 发生和发展的重要促进因子，在 AG 组织和细胞中高度表达。高浓度的 GDNF 通过 GDNF 家族受体 alpha-1（GFRα1）/转染重排原癌基因（RET）/丝裂原活化蛋白激酶（MAPK）/磷酸化环 AMP 反应元件结合蛋白（pCREB）信号通路促进 RA 细胞中 LOXL2 的表达和分泌。GDNF 诱导的 LOXL2 显著促进 RA 和 HA 细胞的增殖和迁移，并增加 RA 细胞中 Ccl2、Gbp5、MMP11、TNN 和其他调节细胞外微环境的基因的表达。我们的结果表明，高浓度的 GDNF 通过 GFRα1/RET/MAPK/pCREB 信号轴激活 LOXL2 的表达和分泌，通过 Ccl2、Gbp5、MMP11、TNN 等分子导致星形胶质细胞细胞外微环境的重塑，最终导致异常的星形胶质细胞增殖和迁移。总之，这些发现表明高浓度的 GDNF 可能通过激活 LOXL2 的表达和分泌促进星形胶质细胞向 AG 细胞的恶性转化。
