title: Elucidating the role of the FoxO3a transcription factor in the IGF-1-induced migration and invasion of uveal melanoma cancer cells.
abstract: Uveal melanoma (UM) is the most common primary intraocular malignant tumor of adults. It has high mortality rate due to liver metastasis. However, the epidemiology and pathogenesis of liver metastasis in UM are not elucidated and there is no effective therapy available for preventing the development of this disease. IGF-1 is a growth factor involved in cell proliferation, malignant transformation and inhibition of apoptosis. In previous report, IGF-1 receptor was found to be highly expressed in UM and this was related to tumor prognosis. FoxO3a is a Forkhead box O (FOXO) transcription factor and a downstream target of the IGF-1R/PI3K/Akt pathway involved in a number of physiological and pathological processes including cancer. However, the role of FoxO3a in UM is unknown. In the present study, we investigated fundamental mechanisms in the growth, migration and invasion of UM and the involvement of FoxO3a. IGF-1 increased the cell viability, invasion, migration and S-G2/M cell cycle phase accumulation of UM cells. Western blot analysis showed that IGF-1 led to activation of Akt and concomitant phosphorylation of FoxO3a. FoxO3a phosphorylation was associated with its translocation into the cytoplasm from the nucleus and its functional inhibition led to the inhibition of expression of Bim and p27, but an increase in the expression of Cyclin D1. The effects of IGF-1 on UM cells were reversed by LY294002 (a PI3K inhibitor) or Akt siRNA, and the overexpression of FoxO3a also attenuated basal invasion and migration of UM. Taken all together, these results suggest that inhibition of FoxO3a by IGF-1 via the PI3K/Akt pathway has an important role in IGF-1 induced proliferation and invasion of UM cells. These findings also support FoxO3a and IGF signaling may represent a valid target for investigating the development of new strategies for the treatment and prevention of the pathology of UM.
authors.affiliation: The School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
authors.forename: Fengxia
authors.initials: F
authors.lastname: Yan
authors.affiliation: The School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
authors.forename: Rifang
authors.initials: R
authors.lastname: Liao
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
authors.forename: Mohd
authors.initials: M
authors.lastname: Farhan
authors.affiliation: Xinhua College and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Tinghuai
authors.initials: T
authors.lastname: Wang
authors.affiliation: Xinhua College and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jiashu
authors.initials: J
authors.lastname: Chen
authors.affiliation: The School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, 20 Cornwall St, Woolloongabba, QLD 4102, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Little
authors.affiliation: The School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; Faculty of Health Sciences, University of Macau, Taipa, Macau, China. Electronic address: wenhuazheng@umac.mo.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zheng
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014604:Uveal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000098943:Uveal Melanoma
chemical_list: D002867:Chromones; C499517:FOXO3 protein, human; D005419:Flavonoids; D000071316:Forkhead Box Protein O3; D007093:Imidazoles; D009025:Morpholines; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: FoxO3a translocation; IGF-1; Metastases; Uveal melanoma