Cancer, eye disorders

Cataract; Cataract 6, multiple Types; Cataract 20, multiple Types; Cataract, age-related cortical, 2

A cataract is an abnormal condition of the eyes characterized by the clouding of the lens, which can detrimentally affect visual acuity. It is predicted that ~50% of Americans over the age of 80 have cataracts and require surgical intervention for the symptomatic improvement. Symptoms of cataracts include blurry vision, faded colour vision, halo around lights, reduced night vision, and double vision. EphA2 is a receptor protein-tyrosine kinase that displays promiscuous binding to membrane-bound ligands of the ephrin-A family on adjacent cells. This signalling interaction regulates integrin-dependent adhesion, cellular migration, proliferation, and differentiation. EphA2 also participates in bone remodeling by directly regulating both osteoclastogenesis and osteoblastogenesis. Several mutations in the EphA2 gene have been observed in cataract patients, including substitution mutations (G948W, T940I, R721Q), a deletion mutation resulting in a frameshift (2915delTG), and splice site mutations. When expressed in a HEK293 cell culture, the R271Q mutant EphA2 protein displayed significantly elevated kinase catalytic activity compared to the wildtype protein, which resulted in a substantial reduction in ERK1/2 activity. Additionally, the R271Q mutant EphA2 protein displayed intracellular retention in certain organelles, which is not observed for wildtype proteins and potentially represents a pathological occurence. In animal studies, mice lacking the EphA2 gene displayed significant opacity of the lens at 3-4 months of development, followed by the formation of murine cataracts at 6-8 months, and eventual rupture of the lens. In addition, EphA2 expression was reported to decrease with age in wild-type mice, indicatingly a potential causal explanation for the predominance of cataracts in the aged population. In murine tissue, EphA2 expression in anterior epithelial cells is low initially, but upregulated as the cells enter differentiation, and is highly expressed in cortical fibre cells, but is absent in the nuclei. Significantly increased expression of Hsp25 (mouse homolog of human heat-shock protein 27, HSP27) has been observed in the lens tissue of EphA2 knockout mice, indicating the presence of excessive cellular stress, misfolded proteins, and potentially the activation of autophagy, which may contribute to the pathogenesis of cataracts.
 

Brainstem glioma

EPHA2 may be an oncoprotein (OP). Signficantly elevated EphA2 expression has been observed in many types of human cancer and appears to be involved in mediating communication between RAS-PI3K/AKT and RAS-MAPK intracellular signalling pathways, which are both known to promote tumorigenesis. Additionally, EphA2 is required for UV-radiation induced apoptosis. UV-radiation is a potent carcinogen responsible for the development of melanoma. However, further characterization of melanoma cell lines revealed either a pro-apoptotic or anti-apoptotic role for EphA2 dependent upon the cellular context. Additionally, studies performed in breast cancer cell lines revealed a link between EphA2 expression levels and changes in cytoskeletal morphology and the recruitment of disintegrin and metalloprotease-10 (MMP10) enzymes, thus suggesting a role for theEphA2 protein in the promotion of tumour invasion and metastasis.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Barrett's esophagus epithelial metaplasia (%CFC= -46, p<0.058); Bladder carcinomas (%CFC= +61, p<0.094); Breast epithelial hyperplastic enlarged lobular units (HELU) (%CFC= -71, p<0.01); Cervical epithelial cancer (%CFC= +81, p<0.016); Cervical cancer (%CFC= +211, p<0.0002); Cervical cancer stage 1B (%CFC= +134, p<0.077); Cervical cancer stage 2A (%CFC= +139, p<0.055); Colon mucosal cell adenomas (%CFC= +49, p<0.004); Colorectal adenocarcinomas (early onset) (%CFC= +68, p<0.063); Oral squamous cell carcinomas (OSCC) (%CFC= -57, p<0.048); Ovary adenocarcinomas (%CFC= +50, p<0.094); Skin fibrosarcomas (%CFC= -55); Skin melanomas - malignant (%CFC= -63, p<0.0001); Skin squamous cell carcinomas (%CFC= +123, p<0.027); and Vulvar intraepithelial neoplasia (%CFC= +117, p<0.002). The COSMIC website notes an up-regulated expression score for EPHA2 in diverse human cancers of 325, which is 0.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 0 for this protein kinase in human cancers was 100% lower than the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.09 % in 25597 diverse cancer specimens. This rate is only 20 % higher than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.39 % in 629 stomach cancers tested; 0.36 % in 1152 large intestine cancers tested; 0.33 % in 805 skin cancers tested; 0.16 % in 934 upper aerodigestive tract cancers tested; 0.12 % in 1942 lung cancers tested.

None > 5 in 20,729 cancer specimens

Nineteen deletions, no insertions or complex mutations are noted on the COSMIC website.