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.

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

“…Examples include the uORFs upstream of amino acid transporter, cationic 1 ( CAT1 ; also known as SLC7A1 ) 124,125 and fibro-blast growth factor 9 ( FGF9 ) 126 IRESs and within the vascular endothelial growth factor A ( VEGFA ) 127 IRES, which are all in mRNAs that encode regulators of differentiation and cell growth. In the CAT1 mRNA, structural remodelling of the 5′ UTR in cis by uORF translation mediates unfolding of inhibitory 5′ UTR structures and a switch to a translationally active state of the IRES structure upon amino acid starvation 124,125,128 (FIG.…”

“…In contrast to IRES activation by uORF translation, uORFs can also repress IRES activity, as seen in the VEGFA 127 and FGF9 (REF. 126) mRNAs. In a VEGFA mRNA isoform, a uORF embedded in the IRES is translated in a cap-independent manner and this uORF suppresses IRES-mediated expression of the main ORF 127 , possibly by unfolding the IRES structure.…”

“…In a VEGFA mRNA isoform, a uORF embedded in the IRES is translated in a cap-independent manner and this uORF suppresses IRES-mediated expression of the main ORF 127 , possibly by unfolding the IRES structure. In the FGF9 mRNA, translation of a uORF upstream of the IRES suppresses FGF9 protein synthesis in normal conditions, whereas hypoxia-induced inhibition of cap-dependent translation and a switch to IRES-dependent translation increases FGF9 protein levels 126 .…”

FGF9/FGFR2 increase cell proliferation by activating ERK1/2, Rb/E2F1, and cell cycle pathways in mouse Leydig tumor cells

“…Many reports have illustrated that FGF9 is essential for steroidogenesis and sex determination . However, abnormal expression of FGF9 is involved in different types of cancers . Studies have also shown that endogenous overexpression of FGF9 might cause lung adenocarcinoma, and microRNA‐140‐5p and microRNA‐26a could suppress FGF9 expression to reduce hepatocellular carcinoma and gastric cancer, respectively .…”

Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients withFGF9upregulation may be resistant to anti-EGFR therapies

“…Abnormal FGF9 has transforming potential in the NIH‐3T3 cell line, and the oncogenic activity of FGF9 has been suggested in brain, lung, ovarian, and prostate cancer . Recently, several studies have shown an association between the FGF9 signal and cell adhesion and motility as well as a positive regulation mechanism via translational activation induced by hypoxia in CRC cell lines . However, limited information is available about the involvement of FGF9 in CRC malignancy, including drug resistance.…”