Expression of HGF and c-Met Proteins in Human Keratoconus Corneas

Abstract

Keratoconus (KC) is a progressive degenerative inflammatory-related disease of the human cornea leading to decreased visual function. The pathogenesis of KC remains to be understood. Recent genetic studies indicate that gene variants of an inflammation-related molecule, hepatocyte growth factor (HGF), are associated with an increased susceptibility for developing KC. However HGF protein expression in KC has not been explored. In this initial study, we investigated late-stage KC and control corneas for the expression of HGF and its receptor mesenchymal-epithelial transition factor (c-Met/Met). KC buttons (~8 mm diameter) (n = 10) and whole control corneas (n = 6) were fixed in 10% formalin or 2% paraformaldehyde, paraffin embedded and sectioned. Sections were immunolabelled with HGF and c-Met antibodies, visualised using immunofluorescence, and examined with scanning laser confocal microscopy. Semiquantitative grading was used to compare HGF and c-Met immunostaining in KC and control corneas. Overall, KC corneas showed increased HGF and c-Met immunostaining compared to controls. KC corneal epithelium displayed heterogeneous moderate-to-strong immunoreactivity for HGF and c-Met, particularly in the basal epithelium adjacent to the cone area. Taken together with the recent genetic studies, our results further support a possible role for HGF/c-Met in the pathogenesis of KC.

Oxidative stress induces dysregulated autophagy in corneal epithelium of keratoconus patients

“…A difference in the expression levels (low, medium, high) of autophagosomal marker LC3 has been shown in KC epithelium, but without clinical disease classification, thereby demonstrating alterations in the autophagic pathway [ 30 ]. Similarly, distorted expression levels of hepatocyte growth factor (HGF) and its receptor mesenchymal-epithelial transition factor (c-Met/Met) have been found in the peripheral and cone regions of KC epithelium [ 31 ]. In KC Grade III, we found a slight increase in LC3 and LAMP1 proteins compared to other clinical grades (I,II) suggesting that accumulation of autophagosome and lysosome or impaired fusion may be responsible for the abnormal dynamics of autophagy in the diseased areas of the cornea.…”

C‐MET–dependent signal transduction mediates retinoblastoma growth by regulating PKM2 nuclear translocation

“…C‐MET is a member of the tyrosine kinase growth factor receptor family, which can be activated by the hepatocyte growth factor (HGF) . The binding of HGF to C‐MET results in receptor dimerization that initiates an intracellular signalling cascade and induces proliferation, motility, adhesion, and tumour cell invasion and metastasis . Previous studies have demonstrated that C‐MET is often overexpressed by gene amplification or mutations in tumours.…”

Keratoconus at a Molecular Level: A Review

“…HGF receptors are also present on stromal cells, although the expression of both the receptor and HGF itself are highest at the center of the cornea (Li and Tseng, ). The distribution of c‐Met and HGF are also affected in keratoconus, becoming less uniform and showing increased presence in the basal epithelia near the cone (You et al, ). The exact effect of HGF and KGF on stromal cells is still unknown due to inconclusive reported evidence (Carrington and Boulton, ).…”