首页> 外文期刊>Oncogene >Microglia-derived TGF-|[beta]| as an important regulator of glioblastoma invasion|[mdash]|an inhibition of TGF-|[beta]|-dependent effects by shRNA against human TGF-|[beta]| type II receptor
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Microglia-derived TGF-|[beta]| as an important regulator of glioblastoma invasion|[mdash]|an inhibition of TGF-|[beta]|-dependent effects by shRNA against human TGF-|[beta]| type II receptor

机译:小胶质细胞衍生的TGF- |β|作为胶质母细胞瘤侵袭的重要调节剂,shRNA抑制TGF- |β|依赖于人类TGF- |β|的作用II型受体

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The invasion of tumor cells into brain tissue is a pathologic hallmark of malignant gliomas and contributes to treatment failures. Diffuse glioblastomas contain numerous microglial cells, which enhance the progression of gliomas; however, factors responsible for invasion-promoting role of microglia are unknown. Transforming growth factor-β (TGF-β) can enhance tumor growth, invasion, angiogenesis and immunosuppression. Antagonizing TGF-β activity has been shown to inhibit tumor invasion in vitro and tumorigenicity, but a systemic inhibition or lack of TGF-β signaling results in acute inflammation and disruption of immune system homeostasis. We developed plasmid-transcribed small hairpin RNAs (shRNAs) to downregulate the TGF-β type II receptor (TβIIR) expression, which effectively inhibited cytokine-induced signaling pathways and transcriptional responses in transiently transfected human glioblastoma cells. Silencing of TβIIR abolished TGF-β-induced glioblastoma invasiveness and migratory responses in vitro. Moreover, tumorigenicity of glioblastoma cells stably expressing TβIIR shRNAs in nude mice was reduced by 50%. Microglia strongly enhanced glioma invasiveness in the co-culture system, but this invasion-promoting activity was lost in glioma cells stably expressing shTβRII, indicating a crucial role of microglia-derived TGF-β in tumor–host interactions. Our results demonstrate a successful targeting of TGF-β-dependent invasiveness and tumorigenicity of glioblastoma cells by RNAi-mediated gene silencing.
机译:肿瘤细胞侵入脑组织是恶性神经胶质瘤的病理标志,并导致治疗失败。弥漫性胶质母细胞瘤含有大量的小胶质细胞,可促进神经胶质瘤的发展。但是,尚不清楚引起小胶质细胞侵袭促进作用的因素。转化生长因子-β(TGF-β)可以增强肿瘤的生长,侵袭,血管生成和免疫抑制。已经显示拮抗TGF-β活性在体外抑制肿瘤侵袭和致瘤性,但是全身性抑制或缺乏TGF-β信号传导导致急性炎症和免疫系统稳态的破坏。我们开发了质粒转录的小发夹RNA(shRNA),以下调TGF-βII型受体(TβIIR)的表达,该表达可有效抑制细胞因子诱导的信号通路和瞬时转染的人类胶质母细胞瘤细胞中的转录反应。 TβIIR的沉默消除了TGF-β诱导的胶质母细胞瘤的体外侵袭性和迁移反应。此外,在裸鼠中稳定表达TβIIRshRNA的胶质母细胞瘤细胞的致瘤性降低了50%。小胶质细胞在共培养系统中强烈增强了神经胶质瘤的侵袭性,但是在稳定表达shTβRII的神经胶质瘤细胞中丧失了这种促进侵袭的活性,这表明小胶质细胞衍生的TGF-β在肿瘤与宿主的相互作用中起着至关重要的作用。我们的结果证明通过RNAi介导的基因沉默成功靶向TGF-β依赖性的胶质母细胞瘤细胞侵袭性和致瘤性。

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