Transcriptional response to hypoxia in human tumors
Transcriptional response to hypoxia in human tumors
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DOI：
10.1093/jnci/93.17.1337
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发表时间：
2001-09-05
影响因子：
10.3
通讯作者：
Riggins, GJ
中科院分区：
文献类型：
--
作者：
Lal, A;Peters, H;Riggins, GJ
背景：实体瘤内缺氧区域的存在与更恶性的肿瘤表型和更差的预后有关。为了获得血液供应并防止细胞损伤和死亡，肿瘤中的缺氧细胞改变了基因表达，导致对治疗的抵抗。为了研究癌细胞适应缺氧的机制，我们寻找新的缺氧诱导基因。方法：采用基因表达系列分析方法，定量分析人胶质母细胞瘤细胞对缺氧的转录反应。通过实时聚合酶链反应测定了一组不同的人类肿瘤细胞系中基因表达对缺氧反应的时程。用哌莫硝唑化学标记人癌的低渗区。免疫组织化学和原位杂交被用来检查基因表达在肿瘤的缺氧区域。结果如下：从24504个独特的转录表达，10个新的缺氧调节基因被检测到，所有诱导，在更大程度上比血管内皮生长因子，缺氧诱导的有丝分裂原，促进血管生长。这些基因也对乳腺癌和结肠癌细胞中的缺氧有反应，并被缺氧诱导因子1激活，缺氧诱导因子1是缺氧反应的关键调节因子。在肿瘤中，基因表达仅限于缺氧区域。诱导基因包括hexabrachion（细胞外基质糖蛋白），斯钙素1（钙稳态蛋白），和血管生成素相关基因。结论：我们已经确定了在缺氧恶性细胞内转录激活的基因，这是理解驱动缺氧反应的复杂相互作用的关键第一步。在我们的缺氧反应基因目录中，有新的缺氧驱动血管生成的候选基因。
Background: The presence of hypoxic regions within solid tumors is associated with a more malignant tumor phenotype and worse prognosis. To obtain a blood supply and protect against cellular damage and death, oxygen-deprived cells in tumors alter gene expression, resulting in resistance to therapy. To investigate the mechanisms by which cancer cells adapt to hypoxia, we looked for novel hypoxia-induced genes. Methods: The transcriptional response to hypoxia in human glioblastoma cells was quantified with the use of serial analysis of gene expression. The time course of gene expression in response to hypoxia in a panel of various human tumor cell lines was measured by real-time polymerase chain reaction. Hypoxic regions of human carcinomas were chemically marked with pimonidazole. Immunohistochemistry and an situ hybridization were used to examine gene expression in the tumor's hypoxic regions. Results: From the 24504 unique transcripts expressed, 10 new hypoxia-regulated genes were detected-all induced, to a greater extent than vascular endothelial growth factor, a hypoxia-induced mitogen that promotes blood vessel growth. These genes also responded to hypoxia in breast and colon cancer cells and were activated by hypoxia-inducible factor 1, a key regulator of hypoxic responses. In tumors, gene expression was limited to hypoxic regions. Induced genes included hexabrachion (an extracellular matrix glycoprotein), stanniocalcin 1 (a calcium homeostasis protein), and an angiopoietin-related gene. Conclusions: We have identified the genes that are transcriptionally activated within hypoxic malignant cells, a crucial first step in understanding the complex interactions driving hypoxia response. Within our catalogue of hypoxia-responsive genes are novel candidates for hypoxia-driven angiogenesis.