尤因肉瘤和骨肉瘤中的缺氧和低血糖：缺氧诱导因子的调节和表型作用。

Hypoxia and hypoglycaemia in Ewing's sarcoma and osteosarcoma: regulation and phenotypic effects of Hypoxia-Inducible Factor.

机构信息

Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Oxford, OX3 7LD, UK.

出版信息

BMC Cancer. 2010 Jul 16;10:372. doi: 10.1186/1471-2407-10-372.

DOI:10.1186/1471-2407-10-372

PMID:20637078

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2918574/

Abstract

BACKGROUND

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.

METHODS

HIF-1alpha and HIF-2alpha 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.

RESULTS

17/56 Ewing's tumours were HIF-1alpha-positive, 15 HIF-2alpha-positive and 10 positive for HIF-1alpha and HIF-2alpha. Expression of HIF-1alpha and cleaved caspase 3 localised to necrotic areas. Hypoxia induced HIF-1alpha and HIF-2alpha in Ewing's and osteosarcoma cell lines while hypoglycaemia specifically induced HIF-2alpha in Ewing's. Downstream transcription was HIF-1alpha-dependent in Ewing's sarcoma, but regulated by both isoforms in osteosarcoma. In both cell types hypoglycaemia reduced cellular proliferation by >or= 45%, hypoxia increased apoptosis and HIF siRNA modulated hypoxic proliferation and migration.

CONCLUSIONS

Co-localisation of HIF-1alpha 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.

摘要

背景

缺氧通过转录因子 HIF（缺氧诱导因子）调节基因表达。关于原发性骨肉瘤中 HIF 的表达和功能知之甚少。我们描述了 Ewing 肉瘤和骨肉瘤中 HIF 的表达和表型效应，以及缺氧、低血糖和 HIF 的影响。

方法

在 Ewing 肿瘤组织阵列上进行 HIF-1alpha 和 HIF-2alpha 的免疫组织化学染色。通过 Western blot、荧光素酶测定和 ELISA 评估 Ewing 肉瘤和骨肉瘤细胞系中 HIF 通路的诱导。评估缺氧、低血糖和同工型特异性 HIF siRNA 对增殖、凋亡和迁移的影响。

结果

在 56 例 Ewing 肿瘤中，有 17 例 HIF-1alpha 阳性，15 例 HIF-2alpha 阳性，10 例 HIF-1alpha 和 HIF-2alpha 阳性。HIF-1alpha 和裂解的 caspase 3 的表达定位于坏死区域。缺氧诱导 Ewing 肉瘤和骨肉瘤细胞系中 HIF-1alpha 和 HIF-2alpha 的表达，而低血糖特异性诱导 Ewing 肉瘤中 HIF-2alpha 的表达。在 Ewing 肉瘤中，下游转录是 HIF-1alpha 依赖性的，但在骨肉瘤中则由两种同工型调节。在这两种细胞类型中，低血糖使细胞增殖减少>or=45%，缺氧增加凋亡，HIF siRNA 调节缺氧增殖和迁移。