尽管seglycin作为细胞内蛋白聚糖的功能作用,多种恶性细胞依赖于其表达和组成型分泌来促进其攻击行为。Serglycin成为胶质母细胞瘤的生物标志物,这是最致命和最难以治疗的脑肿瘤,但是它在这种疾病中的作用还没有完全阐明。在我们的研究中,我们抑制了LN-18胶质母细胞瘤细胞中血清素的内源性水平,以破译其与恶性表型的关系。Serglycin抑制的LN-18(LN-18shSRGN)胶质母细胞瘤细胞经历星形胶质细胞分化,其特征是GFAP的诱导表达,SPARCL-1和蜗牛,同时失去了它们的干性能力。特别是,LN-18shSRGN细胞呈现胶质瘤干细胞相关基因表达和ALDH1活性降低,伴随着集落形成能力的降低。此外,LN-18shSRGN细胞中seglycin的抑制延迟了增殖和迁移速率,体外侵袭潜力和体内肿瘤负荷。LN-18shSRGN细胞中缺乏seglycin后出现G2阻滞,随后细胞周期调节因子的表达减少。LN-18shSRGN细胞还表现出蛋白水解酶如MMP的表达和活性受损,TIMP和uPA,在体外和体内。此外,LN-18shSRGN细胞中sglycin的抑制消除了促瘤信号转导的激活。值得注意的是,LN-18shSRGN细胞显示IL-6、IL-8和CXCR-2的较低表达和分泌水平。伴随,serglycin抑制LN-18shSRGN细胞显示ERK1/2,p38,SRC和STAT-3的磷酸化被抑制,与PI3K/AKT和IL-8/CXCR-2信号传导一起控制LN-18胶质母细胞瘤细胞的侵袭性。总的来说,缺乏serglycin有利于星形细胞的命运转变和较不积极的表型,以多能性丧失为特征,细胞周期的阻滞,降低ECM蛋白水解和促肿瘤信号传导衰减的能力。
Despite the functional role of serglycin as an intracellular proteoglycan, a variety of malignant cells depends on its expression and constitutive secretion to advance their aggressive behavior. Serglycin arose to be a biomarker for glioblastoma, which is the deadliest and most treatment-resistant form of brain tumor, but its role in this disease is not fully elucidated. In our study we suppressed the endogenous levels of serglycin in LN-18 glioblastoma cells to decipher its involvement in their malignant phenotype. Serglycin suppressed LN-18 (LN-18shSRGN) glioblastoma cells underwent astrocytic differentiation characterized by induced expression of GFAP, SPARCL-1 and SNAIL, with simultaneous loss of their stemness capacity. In particular, LN-18shSRGN cells presented decreased expression of glioma stem cell-related genes and ALDH1 activity, accompanied by reduced colony formation ability. Moreover, the suppression of serglycin in LN-18shSRGN cells retarded the proliferative and migratory rate, the invasive potential in vitro and the tumor burden in vivo. The lack of serglycin in LN-18shSRGN cells was followed by G2 arrest, with subsequent reduction of the expression of cell-cycle regulators. LN-18shSRGN cells also exhibited impaired expression and activity of proteolytic enzymes such as MMPs, TIMPs and uPA, both in vitro and in vivo. Moreover, suppression of serglycin in LN-18shSRGN cells eliminated the activation of pro-tumorigenic signal transduction. Of note, LN-18shSRGN cells displayed lower expression and secretion levels of IL-6, IL-8 and CXCR-2. Concomitant, serglycin suppressed LN-18shSRGN cells demonstrated repressed phosphorylation of ERK1/2, p38, SRC and STAT-3, which together with PI3K/AKT and IL-8/CXCR-2 signaling control LN-18 glioblastoma cell aggressiveness. Collectively, the absence of serglycin favors an astrocytic fate switch and a less aggressive phenotype, characterized by loss of pluripotency, block of the cell cycle, reduced ability for ECM proteolysis and pro-tumorigenic signaling attenuation.