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(Investigative Ophthalmology and Visual Science. 2008;49:497-504.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-0975
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Involvement of PI3K/Akt Signaling Pathway in Hepatocyte Growth Factor–Induced Migration of Uveal Melanoma Cells

Mao Ye,1,2,3 Danning Hu,2,4,5 Lili Tu,1,2,3 Xiangtian Zhou,1,2,3 Fan Lu,1,2,3 Bin Wen,1,2,3 Wencan Wu,1,2,3 Yi Lin,1,2,3 Zhonglou Zhou,1,2,3 and Jia Qu1,2,3

1From the School of Ophthalmology and Optometry, Eye Hospital, 2Wenzhou Medical College, and 4Myopia Research Institute, Wenzhou, Zhejiang, People’s Republic of China; the 3State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Wenzhou, Zhejiang, People’s Republic of China; and the 5Tissue Culture Center, New York Eye and Ear Infirmary, New York Medical College, New York, New York.

PURPOSE. Uveal melanoma is the most common primary intraocular malignancy in adult humans. Unlike cutaneous melanoma, uveal melanoma disseminates preferentially to the liver through the hematogenous system. To date, the mechanism underlying this metastatic homing is largely unknown. This study investigated the effect of hepatocyte growth factor (HGF)-triggered signaling pathways to identify the role of HGF and its downstream effectors in inducing the migration of uveal melanoma cells.

METHODS. Migration of uveal melanoma cells was measured by in vitro wound healing and transwell migration assays. The expression and translocation of c-Met were detected using indirect immunofluorescence. The activation of extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathways was analyzed using specific antibodies against phospho-ERK1/2 and phospho-Akt. The impact of HGF treatment on the expression of cell adhesion molecules was measured using Western blotting.

RESULTS. HGF was found to enhance cell migration, and that HGF-induced migration depends on PI3K/Akt pathway. The activation of PI3K/Akt pathway induced by the HGF/c-Met axis is involved in the downregulation of cell adhesion molecules E-cadherin and β-catenin, contributing to the attenuation of cell-cell adhesion and promoting the enhanced motility and migration of uveal melanoma cells. On HGF stimulation, receptor c-Met is translocated to the nucleus in a ligand-dependent manner, suggesting that c-Met may modulate the expression of genes involved in melanoma cell migration.

CONCLUSIONS. Data from this study directly linked the central PI3K/Akt pathway to uveal melanoma migration and pointed to new avenues for therapeutic intervention in hepatic metastasis.






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