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M. Ye, D. Hu, Y. Lin, Z. Zhou, L. Tu, X. Zhou, F. Lu, J. Qu; Hepatocyte Growth Factor Induces Migration of Uveal Melanoma Cells via PI3K/AKT Pathway. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4755.
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© ARVO (1962-2015); The Authors (2016-present)
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, which is the leading cause of death in uveal melanoma patients. To date, the mechanism underlying this liver-homing is largely unknown, but growth factors synthesized in the liver may be implicated. Here we investigated the effect of hepatocyte growth factor (HGF) on uveal melanoma cells migration and clarify the signal pathways that are triggered by HGF.
Uveal melanoma cells migration was measured by in vitro wound healing assay. The effect of HGF on proliferation of uveal melanoma cells was evaluated by a colorimetric 3-4,5-(dimenthyl-thyazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. The expression and translocation of c-Met was detected by indirect immunofluorescence. The activation of ERK1/2, p38 and PI3K/AKT pathways were analyzed using specific antibodies against phosphor-ERK1/2, phosphor-p38 and phosphor-AKT.
When a wound was introduced into subconfluent uveal melanoma cells over the course of 24, 48 and 72 hours, motility and migration of uveal melanoma cells treated with HGF were significantly enhanced compared with untreated cells. However, HGF had no stimulatory effect on the proliferation of uveal melanoma cells. Indirect immunofluorescence showed c-Met, a specific receptor of HGF, translocated to the nucleus from cytoplasm and membrane in HGF-treated uveal melanoma cells. Among the pathway components analyzed, significant and time-dependent activation of AKT was observed, but no significant changes of p38 and ERK1/2 were found by Western blot analysis. LY294002, an ATP-competitive and specific inhibitor of PI3K, could inhibit HGF-induced cell migration in a dose-dependent manner.
Our data show that HGF can enhance motility but not proliferation of uveal melanoma cells. HGF-induced migration is dependent on PI3K/AKT pathway, but independent of ERK1/2 and P38 pathways. We revealed for the first time that HGF receptor, c-Met, localizes to the nucleus in a ligand-dependent manner in uveal melanoma cells, which may play an important role on uveal melanoma migration. Furthermore, the central of PI3K/AKT pathway in uveal melanoma migration may be important for the design of specific therapeutic strategies and future treatments for the control of liver metastasis of uveal melanoma.
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