Sung Fion L, Hui Edwin P, Tao Qian, Li Hongyu, Tsui Nancy B Y, Lo Y M Dennis, Ma Brigette B Y, To Ka F, Harris Adrian L, Chan Anthony T C
Department of Clinical Oncology, State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
Cancer Lett. 2007 Aug 8;253(1):74-88. doi: 10.1016/j.canlet.2007.01.012. Epub 2007 Feb 22.
Previously, we showed that hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, carbonic anhydrase IX (CA IX), and vascular endothelial growth factor (VEGF) were frequently coexpressed in tumor biopsies from patients of nasopharyngeal carcinoma (NPC) and were associated with poor outcome after radiotherapy. Here, we further studied hypoxic induction of HIF-1alpha, HIF-2alpha, CA IX, and VEGF in NPC cell lines, investigated hypoxia-modulated gene expression in NPC cell lines by Affymetrix GeneChip Array expression profiling, and identified pathways influenced by hypoxia and novel genes not previously recognized as hypoxia-inducible. Differentially regulated genes under hypoxia were identified genome widely and selected genes validated by RT-PCR. We found that hypoxia induced HIF-1alpha, CA IX and VEGF expression but not HIF-2alpha in NPC cells. Microarray expression analysis showed that 222 genes were commonly up-regulated and 137 genes down-regulated in hypoxic-treated CNE-2 and HONE-1 cells. Hypoxia induced broad changes of both up- and down-regulated gene expressions involved in diverse biological processes in NPC cells. Elucidation of the coordinated functions modulated by hypoxia could lead to a better understanding of the clinical significance of the hypoxic tumor phenotype.
此前，我们发现缺氧诱导因子（HIF）-1α、HIF-2α、碳酸酐酶IX（CA IX）和血管内皮生长因子（VEGF）在鼻咽癌（NPC）患者的肿瘤活检组织中经常共同表达，且与放疗后的不良预后相关。在此，我们进一步研究了NPC细胞系中HIF-1α、HIF-2α、CA IX和VEGF的缺氧诱导情况，通过Affymetrix基因芯片阵列表达谱研究了NPC细胞系中缺氧调节的基因表达，并确定了受缺氧影响的信号通路以及先前未被认为是缺氧诱导的新基因。在全基因组范围内鉴定了缺氧条件下差异调节的基因，并通过RT-PCR验证了所选基因。我们发现缺氧可诱导NPC细胞中HIF-1α、CA IX和VEGF的表达，但不诱导HIF-2α的表达。微阵列表达分析表明，在缺氧处理的CNE-2和HONE-1细胞中，222个基因普遍上调，137个基因下调。缺氧诱导了NPC细胞中参与多种生物学过程的上调和下调基因表达的广泛变化。阐明缺氧调节的协同功能可能有助于更好地理解缺氧肿瘤表型的临床意义。
