ETS-1 and ETS-2 are upregulated in a transgenic mouse model of pigmented ocular neoplasm.
OBJECTIVE
Choroidal melanoma is the most common primary malignant ocular tumor in human adults. Relevant mouse models of human uveal melanoma still remain to be developed. We have studied the transgenic mouse strain, Tyrp-1-TAg, to try to gain insight into possible molecular mechanisms common to pigmented ocular neoplasms occurring spontaneously in the eyes of these mice and human choroidal melanoma. The role of two members of the ETS (E26 avian leukemia oncogene) family of transcription factors, ETS-1 and ETS-2, has been investigated in many cancers but has not yet been studied in ocular tumors.


METHODS
This is the first study describing the production and distribution of ETS-1 and ETS-2 mRNAs and proteins using in situ hybridization and immunohistochemistry in murine ocular tissue sections of normal control eyes and tumoral eyes from mice of the same age. Using semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) and western blots experiments, we compared changes in ETS-1 and ETS-2 expression, their protein levels, and the regulation of some of their target gene expressions at different stages of the ocular tumoral progression in the transgenic mouse model, Tyrp-1-TAg, with those in normal eyes from control mice of the same age.


RESULTS
In normal control adult mouse eyes, ETS-1 was mostly present in the nuclei of all neuroretinal layers whereas ETS-2 was mostly localized in the cytosol of the cell bodies of these layers with a smaller amount present in the nuclei. Both were found in the retinal pigmentary epithelium (RPE). ETS-1 and ETS-2 mRNA and protein levels were much higher in the ocular tissues of Tyrp-1-TAg mice than in control ocular tissues from wild-type mice. This upregulation was correlated with tumor progression. We also demonstrated upregulation of ETS-1 and ETS-2 target expressions in Tyrp-1-TAg mice when comparing with the same target expressions in control mice.


CONCLUSIONS
Our findings suggest that ETS-1 and ETS-2 are upregulated in ocular tumors derived from the retinal epithelium and may be involved in one or several signaling pathways that activate the expression of a set of genes involved in ocular tumor progression such as those encoding ICAM-1 (intercellular adhesion molecule-1), PAI-1 (Plasminogen activator inhibitor-1), MCP-1 (monocyte chemoattractant protein-1) and p16 (Cyclin dependent kinase inhibitor 2A).
De la Houssaye
G
G
Université Paris-Descartes, Centre de Recherches Théapeutiques en Ophtalmologie de la Facultéde Méecine Paris-Descartes-site Necker (CERTO), AP-HP, Hôpital Necker Enfants-Malades, Paris, France.
Vieira
V
V
Masson
C
C
Beermann
F
F
Dufier
J L
JL
Menasche
M
M
Abitbol
M
M
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005123:Eye / Q000378:metabolism / Q000473:pathology; D005134:Eye Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010858:Pigmentation / Q000235:genetics*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics* / Q000378:metabolism; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D019941:Cyclin-Dependent Kinase Inhibitor p16; C494042:Ets1 protein, mouse; C494070:Ets2 protein, mouse; D017395:Plasminogen Activator Inhibitor 1; D050784:Proto-Oncogene Protein c-ets-1; D050787:Proto-Oncogene Protein c-ets-2; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1