Post-translational MYC stabilization in association with IGF-1 signaling during corneal epithelial repair.

Corneal ulcers are common in both humans and companion animals and involve epithelial or stromal defects that may progress to sight-threatening scarring or globe perforation. Both insulin-like growth factor-1 (IGF-1) signaling pathways and MYC-mediated cellular programs promote corneal epithelial proliferation and migration imperative for uncomplicated wound resolution; however, the role of IGF-1 in the regulation of MYC during corneal epithelial repair has not been characterized. The objective of this study was to examine IGF-1-mediated MYC expression in the corneal epithelium using telomerase-immortalized human corneal epithelial (hTCEpi) cells, ex vivo human corneas, and adult wildtype C57B6 mice. IGF-1 signaling was pharmacologically modulated using small molecule agonists and antagonists of the IGF-1 receptor (IGF1R) before expression of MYC, and effector kinases downstream in the IGF-1 signaling pathway, were evaluated. Additional assessments of morphology, wound restoration, proliferation, and apoptosis were pursued. Myc expression was also evaluated in archival enucleation specimens of naturally occurring corneal ulceration in canine globes. Activation of IGF-1 signaling promoted MYC expression in all three experimental models and MYC stability in hTCEpi cells. This upregulation of MYC was associated with significantly improved wound restoration and increased proliferation rates. MYC and IGF-1 inhibition yielded the inverse phenotype with significantly increased apoptosis. Myc was also upregulated in canine corneas with deep stromal ulceration associated with keratitis and descemetoceles, while Myc expression was attenuated in superficial ulcers constrained to the epithelium. Collectively, these results identify the IGF-1 pathway as a putative correlate of altered MYC expression during corneal epithelial repair.