Niizeki H, Kobayashi M, Horiuchi I, Akakura N, Chen J, Wang J, Hamada J-i, Seth P, Katoh H, Watanabe H, Raz A, Hosokawa M
Division of Cancer Pathobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
Br J Cancer. 2002 Jun 17;86(12):1914-9. doi: 10.1038/sj.bjc.6600331.
The incidence of distant metastases is higher in the tumours with low oxygen pressure than in those with high oxygen pressure. It is well known that hypoxia induces the transcription of various genes involved in angiogenesis and anaerobic metabolism necessary for the growth of tumour cells in vivo, suggesting that hypoxia may also induce the transcription of metastasis-associated genes. We sought to identify the metastasis-associated genes differentially expressed in tumour cells under hypoxic conditions with the use of a DNA microarray system. We found that hypoxia enhanced the expression of autocrine motility factor mRNA in various cancer cells and also enhanced the random motility of pancreatic cancer cells. Autocrine motility factor inhibitors abrogated the increase of motility under hypoxic conditions. In order to explore the roles of hypoxia-inducible factor-1alpha, we established hypoxia-inducible factor-1alpha-transfectants and dominant negative hypoxia-inducible factor-1alpha-transfectants. Transfection with hypoxia-inducible factor-1alpha and dominant-negative hypoxia-inducible factor-1alpha enhanced and suppressed the expression of autocrine motility factor/phosphohexase isomerase/neuroleukin mRNA and the random motility, respectively. These results suggest that hypoxia may promote the metastatic potential of cancer cells through the enhanced autocrine motility factor/phosphohexase isomerase/neuroleukin mRNA expression and that the disruption of the hypoxia-inducible factor-1 pathway may be an effective treatment for metastasis.
低氧压力肿瘤中远处转移的发生率高于高氧压力肿瘤。众所周知，缺氧可诱导体内肿瘤细胞生长所需的各种参与血管生成和无氧代谢的基因转录，这表明缺氧也可能诱导转移相关基因的转录。我们试图利用DNA微阵列系统鉴定在缺氧条件下肿瘤细胞中差异表达的转移相关基因。我们发现缺氧增强了各种癌细胞中自分泌运动因子mRNA的表达，也增强了胰腺癌细胞的随机运动能力。自分泌运动因子抑制剂消除了缺氧条件下运动能力的增加。为了探究缺氧诱导因子-1α的作用，我们构建了缺氧诱导因子-1α转染细胞和显性负性缺氧诱导因子-1α转染细胞。分别用缺氧诱导因子-1α和显性负性缺氧诱导因子-1α转染可增强和抑制自分泌运动因子/磷酸己糖异构酶/神经白细胞素mRNA的表达以及随机运动能力。这些结果表明，缺氧可能通过增强自分泌运动因子/磷酸己糖异构酶/神经白细胞素mRNA的表达来促进癌细胞的转移潜能，并且破坏缺氧诱导因子-1途径可能是一种有效的转移治疗方法。
