Huang Xin, Ding Lianghao, Bennewith Kevin L, Tong Ricky T, Welford Scott M, Ang K Kian, Story Michael, Le Quynh-Thu, Giaccia Amato J
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94025, USA.
Mol Cell. 2009 Sep 24;35(6):856-67. doi: 10.1016/j.molcel.2009.09.006.
Previous studies have suggested that the HIF transcription factors can both activate and inhibit gene expression. Here we show that HIF1 regulates the expression of mir-210 in a variety of tumor types through a hypoxia-responsive element. Expression analysis in primary head and neck tumor samples indicates that mir-210 may serve as an in vivo marker for tumor hypoxia. By Argonaute protein immunoprecipitation, we identified 50 potential mir-210 targets and validated randomly selected ones. The majority of these 50 genes are not classical hypoxia-inducible genes, suggesting mir-210 represses genes expressed under normoxia that are no longer necessary to adapt and survive in a hypoxic environment. When human head and neck or pancreatic tumor cells ectopically expressing mir-210 were implanted into immunodeficient mice, mir-210 repressed initiation of tumor growth. Taken together, these data implicate an important role for mir-210 in regulating the hypoxic response of tumor cells and tumor growth.
以往的研究表明，低氧诱导因子（HIF）转录因子既能激活基因表达，也能抑制基因表达。在此我们发现，HIF1通过缺氧反应元件调控多种肿瘤类型中mir-210的表达。对头颈部原发性肿瘤样本的表达分析表明，mir-210可能作为肿瘤缺氧的体内标志物。通过AGO蛋白免疫沉淀，我们鉴定出50个潜在的mir-210靶标，并对随机选择的靶标进行了验证。这50个基因中的大多数并非经典的缺氧诱导基因，提示mir-210抑制在常氧下表达、而在缺氧环境中适应和存活不再必需的基因。当将异位表达mir-210的人源头颈部或胰腺肿瘤细胞植入免疫缺陷小鼠体内时，mir-210抑制肿瘤生长的起始。综上所述，这些数据表明mir-210在调节肿瘤细胞的缺氧反应及肿瘤生长中发挥重要作用。
