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

Tsung-Ming Chen,Yu-Heng Shih,H Sunny Sun,Joseph T Tseng,Shaw-Jenq Tsai,Chih-Hao Wu,Yi-Han Li,Ming-Chih Lai

doi:10.1093/nar/gkt1286

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.

Highlights

The fibroblast growth factor (FGF) family includes at least 24 distinct polypeptides with molecular masses ranging from 17 to 34 kDa and share 13–71% sequence identity [1]
To test whether the net effect of hypoxia was attributable to an increase in translational efficacy, fibroblast growth factor 9 (FGF9) protein levels were normalized to the messenger RNA (mRNA) levels at the same time point
The protein-to-mRNA ratios did not change during the 36 h of normoxia (Figure 1C; P = 0.42), but there was a rise in FGF9 protein levels in the hypoxic cells (P < 0.001)

Summary

Introduction

The fibroblast growth factor (FGF) family includes at least 24 distinct polypeptides with molecular masses ranging from 17 to 34 kDa and share 13–71% sequence identity [1]. Many mammalian FGFs are abundantly expressed in a specific spatial and temporal pattern and are substantially involved in many cellular processes, including development [2] and angiogenesis [3]. Previous reports demonstrated that FGF9 acts as an autocrine and/or paracrine growth factor for many different types of cells, such as neurons [6,7], uterine endometrial stroma [8,9] and fibroblasts [10]. FGF9 is vital for many key processes, including development of the lungs [11] and bone [12], and for steroidogenesis in postnatal Leydig cells [13]

Methods

Results

Conclusion