Hypoxia inhibits growth, proliferation, and increases response to chemotherapy in retinoblastoma cells
Hypoxia inhibits growth, proliferation, and increases response to chemotherapy in retinoblastoma cells
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DOI：
10.1016/j.exer.2017.07.001
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发表时间：
2017-09-01
影响因子：
3.4
通讯作者：
Asnaghi, Lalira
中科院分区：
文献类型：
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作者：
Yang, Qian;Tripathy, Arushi;Asnaghi, Lalira
视网膜母细胞瘤是一种视网膜恶性肿瘤，也是儿童中最常见的眼内癌。低氧张力（缺氧）是晚期视网膜母细胞瘤的常见现象，但其对视网膜母细胞瘤生长的生物学作用尚不清楚。在这里，我们研究了缺氧如何改变视网膜母细胞瘤基因表达并调节生长和对化疗的反应。通过免疫组织化学分析，12 个人类视网膜母细胞瘤中有 8 个表达缺氧标记物赖氨酰氧化酶 (LOX)，这表明多达三分之二的病例存在缺氧微环境。 WERI Rb1 和 Y79 视网膜母细胞瘤系暴露于 1% 或 5% pO(2)、氯化钴 (CoCl2) 或常氧 (21% pO(2)) 中长达 8 天。 1% 和 5% pO(2) 均可抑制两种品系的生长 50% 以上。根据 Ki67 测定，当视网膜母细胞瘤细胞暴露于 1% 与 21% pO(2) 时，增殖减少 25-50%。令人惊讶的是，与常氧细胞相比，美法仑、卡铂和依托泊苷对缺氧细胞的生长和存活的抑制更大。对暴露于 1%、5% 或 21% pO(2) 48 小时的两个品系的基因表达谱分析表明，与常氧相比，糖酵解和葡萄糖转运是缺氧条件下最上调的途径，而氧化磷酸化是缺氧条件下最下调的途径。这些数据支持缺氧在抑制生长、增殖和增强视网膜母细胞瘤细胞对化疗的反应方面的作用，可能是通过激活糖酵解和抑制线粒体呼吸来损害能量产生。针对葡萄糖代谢或增强化疗药物向缺氧区域的输送可能会改善晚期视网膜母细胞瘤的治疗。 (C) 2017 Elsevier Ltd. 保留所有权利。
Retinoblastoma is a malignant tumor of the retina and the most frequent intraocular cancer in children. Low oxygen tension (hypoxia) is a common phenomenon in advanced retinoblastomas, but its biological effect on retinoblastoma growth is not clearly understood. Here we studied how hypoxia altered retinoblastoma gene expression and modulated growth and response to chemotherapy. The hypoxic marker lysyl oxidase (LOX) was expressed in 8 of 12 human retinoblastomas analyzed by immunohistochemistry, suggesting that a hypoxic microenvironment is present in up to two thirds of the cases. WERI Rb1 and Y79 retinoblastoma lines were exposed to 1% or 5% pO(2), cobalt chloride (CoCl2), or to normoxia (21% pO(2)) for up to 8 days. Both 1% and 5% pO(2) inhibited growth of both lines by more than 50%. Proliferation was reduced by 25-50% when retinoblastoma cells were exposed to 1% vs 21% pO(2), as determined by Ki67 assay. Surprisingly, Melphalan, Carboplatin, and Etoposide produced greater reduction in growth and survival of hypoxic cells than normoxic ones. Gene expression profile analysis of both lines, exposed for 48 h to 1%, 5%, or 21% pO(2), showed that glycolysis and glucose transport were the most up-regulated pathways, whereas oxidative phosphorylation was the most down-regulated pathway in hypoxia as compared to normoxia. These data support a role for hypoxia in suppressing growth, proliferation, and enhancing response of retinoblastoma cells to chemotherapy, possibly by impairing energy production through activation of glycolysis and inhibition of mitochondrial respiration. Targeting glucose metabolism or enhancing delivery of chemotherapeutic agents to hypoxic regions may improve treatment of advanced retinoblastomas. (C) 2017 Elsevier Ltd. All rights reserved.