title: Overexpression of FGF9 in colon cancer cells is mediated by hypoxia-induced translational activation.
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.
authors: 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.
authors: Tsung-Ming
authors: TM
authors: Chen
authors: Yu-Heng
authors: YH
authors: Shih
authors: Joseph T
authors: JT
authors: Tseng
authors: Ming-Chih
authors: MC
authors: Lai
authors: Chih-Hao
authors: CH
authors: Wu
authors: Yi-Han
authors: YH
authors: Li
authors: Shaw-Jenq
authors: SJ
authors: Tsai
authors: H Sunny
authors: HS
authors: Sun
mesh_terms: D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D051525:Fibroblast Growth Factor 9 / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D010442:Peptide Chain Initiation, Translational; D014176:Protein Biosynthesis; D038621:Regulatory Sequences, Ribonucleic Acid
chemical_list: C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; D038621:Regulatory Sequences, Ribonucleic Acid