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 beta-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.
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 beta-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.
Authors: Peter V Usatyuk; Panfeng Fu; Vijay Mohan; Yulia Epshtein; Jeffrey R Jacobson; Julian Gomez-Cambronero; Kishore K Wary; Vytas Bindokas; Steven M Dudek; Ravi Salgia; Joe G N Garcia; Viswanathan Natarajan Journal: J Biol Chem Date: 2014-03-14 Impact factor: 5.157
Authors: Robert M Gemmill; Patrick Nasarre; Joyce Nair-Menon; Federico Cappuzzo; Lorenza Landi; Armida D'Incecco; Hidetaka Uramoto; Takeshi Yoshida; Eric B Haura; Kent Armeson; Harry A Drabkin Journal: Sci Signal Date: 2017-01-17 Impact factor: 8.192
Authors: Pinar Kanlikilicer; Mohammed H Rashed; Recep Bayraktar; Rahul Mitra; Cristina Ivan; Burcu Aslan; Xinna Zhang; Justyna Filant; Andreia M Silva; Cristian Rodriguez-Aguayo; Emine Bayraktar; Martin Pichler; Bulent Ozpolat; George A Calin; Anil K Sood; Gabriel Lopez-Berestein Journal: Cancer Res Date: 2016-10-14 Impact factor: 12.701
Authors: Christopher P Gayer; Lakshmi S Chaturvedi; Shouye Wang; Brittany Alston; Thomas L Flanigan; Marc D Basson Journal: Am J Physiol Gastrointest Liver Physiol Date: 2009-01-29 Impact factor: 4.052
Authors: Mehrnoosh Saghizadeh; Andrei A Kramerov; Fu-Shin X Yu; Maria G Castro; Alexander V Ljubimov Journal: Invest Ophthalmol Vis Sci Date: 2009-11-20 Impact factor: 4.799