低氧是肿瘤生长必然经历的重要微环境，被认为是肿瘤恶性转化的重要诱因之一。课题组在前期研究中发现低氧下肿瘤细胞eIF4E的功能活性显著变化，且与其增殖密切相关；基于这些新发现，我们应用荧光滴定技术筛选发现了一类结构全新的小分子eIF4E抑制剂；体内外实验已初步证实其具有较好的低氧选择性抗肿瘤活性，且可在转录后水平调控HIF-1α蛋白的表达。本课题将在此基础上以小分子eIF4E抑制剂作为分子探针，从分子、细胞、模型动物三个层面评价其抗肿瘤分子机制，并进一步深入探讨低氧下eIF4E调控HIF-1α蛋白表达的独特作用机制。本课题的顺利开展一方面有望阐明低氧环境下调控eIF4E功能活性的信号网络及其生物学效应，揭示低氧关键蛋白HIF-1α转录后调控的新模式；另一方面也可明确小分子eIF4E抑制剂的抗肿瘤活性，为以该靶点研发抗肿瘤药物提供崭新的研究思路，因此具有重要的理论意义和广阔的应用价值。

Hypoxia is the essential microenvironment for tumor development, and is considered as one of the most important factors to induce malignant tumor progression. In our preliminary studies, we found that the activity of eIF4E changed significantly in response to tumor hypoxia, which was closely related with tumor cell proliferation. Based on these new findings, with fluorescence titration screening technique we discovered a novel kind of small-molecule eIF4E inhibitors. These compounds with wholly new structure exhibited high hypoxia-selective anti-tumor activity in vitro and in vivo. Also they were shown to be able to regulate the protein expression of HIF-1α at the post-transcriptional level. On these bases, we will employ the small-molecule eIF4E inhibitors as the molecular probes to explore their anti-tumor mechanisms at the molecular and cellular levels as well as in the animal model. Also the special mechanism involved in the regulation of HIF-1α by eIF4E under hypoxia will be further studied. This project is meaningful to demonstrate the signaling networks regulating the activity of eIF4E and its biological effects in hypoxia; a novel molecular event of regulating the expression of HIF-1α post-transcriptionally will be revealed. And also，this research will contribute greatly to make clear the anti-tumor activity of small-molecule eIF4E inhibitors, and will provide new clues to discover and develop novel anti-tumor drugs based on this target.