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Nucleic Acids Res. 2014 Mar;42(5):2932-44. doi: 10.1093/nar/gkt1286. Epub 2013 Dec 10.

Overexpression of FGF9 in colon cancer cells is mediated by hypoxia-induced translational activation.

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1
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.

Abstract

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.

PMID:
24334956
PMCID:
PMC3950685
DOI:
10.1093/nar/gkt1286
[Indexed for MEDLINE]
Free PMC Article
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