Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Institute of Bioinformatics and Biosignaling, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan and Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
Nucleic Acids Res. 2014 Mar;42(5):2932-44. doi: 10.1093/nar/gkt1286. Epub 2013 Dec 10.
Human fibroblast growth factor 9 (FGF9) is a potent mitogen involved in many physiological processes. Although FGF9 messenger RNA (mRNA) is ubiquitously expressed in embryos, FGF9 protein expression is generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in human malignancies including cancers, but the mechanism remains largely unknown. Here, we report that FGF9 protein, but not mRNA, was increased in hypoxia. Two sequence elements, the upstream open reading frame (uORF) and the internal ribosome entry site (IRES), were identified in the 5' UTR of FGF9 mRNA. Functional assays indicated that FGF9 protein synthesis was normally controlled by uORF-mediated translational repression, which kept the protein at a low level, but was upregulated in response to hypoxia through a switch to IRES-dependent translational control. Our data demonstrate that FGF9 IRES functions as a cellular switch to turn FGF9 protein synthesis 'on' during hypoxia, a likely mechanism underlying FGF9 overexpression in cancer cells. Finally, we provide evidence to show that hypoxia-induced translational activation promotes FGF9 protein expression in colon cancer cells. Altogether, this dynamic working model may provide a new direction in anti-tumor therapies and cancer intervention.
人成纤维细胞生长因子 9（FGF9）是一种有效的有丝分裂原，参与许多生理过程。尽管 FGF9 信使 RNA（mRNA）在胚胎中广泛表达，但 FGF9 蛋白表达通常较低，仅限于少数成年器官。FGF9 的异常表达通常导致人类恶性肿瘤，包括癌症，但机制仍不清楚。在这里，我们报告 FGF9 蛋白而不是 mRNA 在缺氧时增加。在 FGF9 mRNA 的 5'UTR 中鉴定出两个序列元件，上游开放阅读框（uORF）和内部核糖体进入位点（IRES）。功能分析表明，FGF9 蛋白合成通常受 uORF 介导的翻译抑制控制，该抑制将蛋白保持在低水平，但通过切换到 IRES 依赖性翻译控制，在缺氧时被上调。我们的数据表明，FGF9 IRES 作为一种细胞开关，在缺氧时将 FGF9 蛋白合成“开启”，这可能是癌细胞中 FGF9 过表达的潜在机制。最后，我们提供了证据表明，缺氧诱导的翻译激活促进了结肠癌细胞中 FGF9 蛋白的表达。总之，这个动态工作模型可能为抗肿瘤治疗和癌症干预提供了一个新的方向。
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