Autocrine endothelin-3/endothelin receptor B signaling maintains cellular and molecular properties of glioblastoma stem cells.
Autocrine endothelin-3/endothelin receptor B signaling maintains cellular and molecular properties of glioblastoma stem cells.
复制标题
DOI：
10.1158/1541-7786.mcr-10-0563
复制
发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Tso CL
中科院分区：
文献类型：
--
作者：
Liu Y;Ye F;Yamada K;Tso JL;Zhang Y;Nguyen DH;Dong Q;Soto H;Choe J;Dembo A;Wheeler H;Eskin A;Schmid I;Yong WH;Mischel PS;Cloughesy TF;Kornblum HI;Nelson SF;Liau LM;Tso CL
胶质母细胞瘤干细胞（GSC）表达放射状胶质细胞（RGC）和神经嵴细胞（NCC）相关基因。我们报告内皮素3（EDN 3），NCC的发展和迁移的一个必不可少的有丝分裂原，是由GSC高度生产。血清诱导的增殖分化迅速降低EDN 3的产生，下调干细胞相关基因的表达，并诱导了两种胶质母细胞瘤标志物EDN 1和YKL-40转录物的表达。相应地，患者胶质母细胞瘤组织表达低水平的EDN 3 mRNA和高水平的EDN 1和YKL-40 mRNA。通过EDNRB拮抗剂（BQ 788）或EDN 3 RNA干扰（siRNA）阻断EDN 3/内皮素受体B（EDNRB）信号传导导致细胞凋亡和培养物中肿瘤球形成和细胞扩散/迁移的功能损害，以及动物中致瘤能力的丧失。使用外源性EDN 3作为培养物中的唯一有丝分裂原不支持GSC增殖，但可以拯救GSC免于细胞凋亡。通过基因表达谱的分子分析显示，EDN 3/EDNRB阻断下调的大多数基因涉及细胞骨架组织、生长和分化暂停以及DNA损伤反应，暗示EDN 3/EDNRB信号转导参与维持GSC迁移、未分化和存活。这些数据表明，自分泌EDN 3/EDNRB信号传导对于维持GSC是必需的。将END 3/EDNRB靶向治疗纳入常规癌症治疗可能对预防肿瘤复发具有临床意义。
Glioblastoma stem cells (GSC) express both radial glial cell (RGC) and neural crest cell (NCC)-associated genes. We report that endothelin 3 (EDN3), an essential mitogen for NCC development and migration, is highly produced by GSC. Serum-induced proliferative differentiation rapidly decreased EDN3 production and downregulated the expression of stemness-associated genes, and reciprocally, two glioblastoma markers, EDN1 and YKL-40 transcripts, were induced. Correspondingly, patient glioblastoma tissues express low levels of EDN3 mRNA and high levels of EDN1 and YKL-40 mRNA. Blocking EDN3/endothelin receptor B (EDNRB) signaling by an EDNRB antagonist (BQ788), or EDN3 RNA interference (siRNA), leads to cell apoptosis and functional impairment of tumor-sphere formation and cell spreading/migration in culture, and loss of tumorigenic capacity in animals. Using exogenous EDN3 as the sole mitogen in culture does not support GSC propagation, but can rescue GSC from undergoing cell apoptosis. Molecular analysis by gene expression profiling revealed that most genes downregulated by EDN3/EDNRB blockade were those involved in cytoskeleton organization, pause of growth and differentiation, and DNA damage response, implicating the involvement of EDN3/EDNRB signaling in maintaining GSC migration, undifferentiation, and survival. These data suggest that autocrine EDN3/EDNRB signaling is essential for maintaining GSC. Incorporating END3/EDNRB-targeted therapies into conventional cancer treatments may have clinical implication for the prevention of tumor recurrence.