Hypoxia and hypoglycaemia in Ewing's sarcoma and osteosarcoma: regulation and phenotypic effects of Hypoxia-Inducible Factor.
Hypoxia and hypoglycaemia in Ewing's sarcoma and osteosarcoma: regulation and phenotypic effects of Hypoxia-Inducible Factor.
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DOI：
10.1186/1471-2407-10-372
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发表时间：
2010-07-16
期刊：
影响因子：
3.8
通讯作者：
Athanasou NA
中科院分区：
文献类型：
--
作者：
Knowles HJ;Schaefer KL;Dirksen U;Athanasou NA
缺氧通过转录因子HIF（缺氧诱导因子）调节基因表达。关于HIF在原发性骨肉瘤中的表达和功能知之甚少。我们描述了缺氧诱导因子在尤文肉瘤和骨肉瘤中的表达以及缺氧、低血糖和缺氧诱导因子的表型效应。HIF-1α和HIF-2α免疫组化在Ewing肿瘤组织阵列上进行。通过蛋白质印迹、荧光素酶测定和ELISA评估尤因肉瘤和骨肉瘤细胞系的HIF途径诱导。评估缺氧、低血糖和亚型特异性HIF siRNA对增殖、凋亡和迁移的影响。56例尤文氏瘤中17例HIF-1α阳性，15例HIF-2α阳性，10例HIF-1α和HIF-2α均阳性。HIF-1α和切割的caspase 3的表达定位于坏死区。低氧诱导尤文氏细胞和骨肉瘤细胞中的HIF-1α和HIF-2α，而低血糖特异性诱导尤文氏细胞中的HIF-2α。在尤文氏肉瘤中，下游转录是HIF-1α依赖的，但在骨肉瘤中受两种亚型的调控。在两种细胞类型中，低血糖使细胞增殖降低≥ 45%，缺氧增加细胞凋亡，HIF siRNA调节缺氧增殖和迁移。尤文肉瘤中HIF-1α和坏死的共定位表明缺氧和/或低血糖在体内诱导HIF中的作用。体外数据表明缺氧是尤文氏瘤和骨肉瘤中主要的HIF刺激，对增殖和凋亡有驱动作用。这些结果为进一步了解HIF在原发性骨肉瘤病理生物学中的作用提供了基础。
Hypoxia regulates gene expression via the transcription factor HIF (Hypoxia-Inducible Factor). Little is known regarding HIF expression and function in primary bone sarcomas. We describe HIF expression and phenotypic effects of hypoxia, hypoglycaemia and HIF in Ewing's sarcoma and osteosarcoma. HIF-1α and HIF-2α immunohistochemistry was performed on a Ewing's tumour tissue array. Ewing's sarcoma and osteosarcoma cell lines were assessed for HIF pathway induction by Western blot, luciferase assay and ELISA. Effects of hypoxia, hypoglycaemia and isoform-specific HIF siRNA were assessed on proliferation, apoptosis and migration. 17/56 Ewing's tumours were HIF-1α-positive, 15 HIF-2α-positive and 10 positive for HIF-1α and HIF-2α. Expression of HIF-1α and cleaved caspase 3 localised to necrotic areas. Hypoxia induced HIF-1α and HIF-2α in Ewing's and osteosarcoma cell lines while hypoglycaemia specifically induced HIF-2α in Ewing's. Downstream transcription was HIF-1α-dependent in Ewing's sarcoma, but regulated by both isoforms in osteosarcoma. In both cell types hypoglycaemia reduced cellular proliferation by ≥ 45%, hypoxia increased apoptosis and HIF siRNA modulated hypoxic proliferation and migration. Co-localisation of HIF-1α and necrosis in Ewing's sarcoma suggests a role for hypoxia and/or hypoglycaemia in in vivo induction of HIF. In vitro data implicates hypoxia as the primary HIF stimulus in both Ewing's and osteosarcoma, driving effects on proliferation and apoptosis. These results provide a foundation from which to advance understanding of HIF function in the pathobiology of primary bone sarcomas.
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影响因子：
5
作者：
Batra, S;Perelman, N;Malik, P
通讯作者：
Malik, P
影响因子：
3.3
作者：
KISSANE, JM;ASKIN, FB;SHIRLEY, SF
通讯作者：
SHIRLEY, SF
影响因子：
5.3
作者：
Brunelle, Joslyn K.;Shroff, Emelyn H.;Chandel, Navdeep S.
通讯作者：
Chandel, Navdeep S.
影响因子：
5.3
作者：
Halterman, MW;Miller, CC;Federoff, HJ
通讯作者：
Federoff, HJ
影响因子：
11.5
作者：
Guan, H;Jia, SF;Kleinerman, ES
通讯作者：
Kleinerman, ES