Differential regulation of Dlg1, Scrib, and Lgl1 expression in a transgenic mouse model of ocular cancer.
OBJECTIVE
Discs large (dlg), scribble (scrib), and lethal giant larvae (lgl) are major suppressor genes in Drosophila melanogaster. They encode proteins that regulate cell polarity and cell proliferation in Drosophila and mammals. However, their basic oncogenic roles have not yet been established in mouse epithelial ocular cancer. We evaluated the potential implication of these proteins in tumorigenesis of adenocarcinomas originating from the retinal pigmented epithelium of the Trp1/Tag transgenic mouse model. We examined the changes in the distribution and levels of these proteins in mouse ocular tissues from the Trp1/Tag mouse model.


METHODS
The expression patterns of theses genes and their corresponding proteins in normal mouse ocular tissues were studied by in situ hibridization and immunohistofluorescence experiments. In addition, variations in mRNA and proteins levels and protein distributions for Dlg1, Scrib, and Lgl1 were analyzed in the ocular tissues from Trp1/Tag transgenic mouse model by reverse transcription polymerase chain reaction (RT-PCR), western blot analysis, and immunohistofluorescence.


RESULTS
We found that mouse Dlg1, Scrib, and Lgl1 are widely distributed in normal ocular tissues, particularly in retinal neurons. We found that the three proteins are mislocalized in retinal layers during ocular carcinogenesis. These mislocalizations were correlated to the early dysplastic stages of ocular tumorigenesis. Additionally, the mislocalization of each protein was associated with its downregulation. Decreased levels of these proteins may be considered as late-stage markers of the disease but also as markers of the invasive stage of this cancerous process. This downregulation may be involved in epithelial-mesenchymal transition in this mouse ocular tumoral model. This would be consistent with the downregulation of E-cadherin and upregulation of N-cadherin expression observed in this model.


CONCLUSIONS
This is the first study to demonstrate the involvement of Dlg1, Scrib, and Lgl1 in a mouse with ocular adenocarcinoma and the simultaneous involvement of these proteins in the same cancer. Our results indicate that both the mislocalization and downregulation of these proteins may be involved together in ocular carcinogenesis.
Vieira
V
V
Université Paris-Descartes, CERTO, Centre de Recherches Thérapeutiques en Ophtalmologie de Faculté de Médecine Paris- Descartes-site Necker, EA no2502 du Ministère de Recherche, AP-HP, Paris, France.
de la Houssaye
G
G
Lacassagne
E
E
Dufier
J L
JL
Jaïs
J P
JP
Beermann
F
F
Menasche
M
M
Abitbol
M
M
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D000074288:Discs Large Homolog 1 Protein; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D005134:Eye Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics*; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D000074407:SAP90-PSD95 Associated Proteins; D014158:Transcription, Genetic
D015820:Cadherins; D000074288:Discs Large Homolog 1 Protein; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000074407:SAP90-PSD95 Associated Proteins; C000614189:Dlg1 protein, mouse; C524369:LGL1 protein, mouse; C508433:scrib protein, mouse