title: Mutant GNAQ promotes cell viability and migration of uveal melanoma cells through the activation of Notch signaling.
abstract: The occurrence of guanine nucleotide binding protein (G protein), q polypeptide (GNAQ) mutations has been found to be high in the majority of uveal melanomas. However, the underlying molecular mechanism of GNAQ mutations in modulating uveal melanoma is poorly understood. The aim of the present study was to investigate the role and underlying mechanism of mutant GNAQ in the regulation of cell viability and migration of uveal melanoma cells. Uveal melanoma cells containing mutant GNAQ were transfected with scrambled or GNAQ small-interfering RNA. Compared with the control, GNAQ knockdown markedly inhibited cell viability and migration. However, tumor cells without GNAQ mutations exhibited enhanced viability and migration following transfection with HA-GαqQL. Additionally, GNAQ knockdown significantly downregulated the expression of Jag-1 (Notch ligand), Notch intracellular domain and Hes-1 (Notch target gene) in uveal melanoma cells. Conversely, the GNAQ overexpression promoted their expression. Cell viability and migration induced by GNAQ was significantly inhibited following treatment with 5 µmol/l MRK003, a Notch signaling inhibitor. Furthermore, the transfection of human influenza hemagglutinin A epitope (HA)-GαqQL into tumor cells caused Yes-associated protein (YAP) dephosphorylation and nuclear translocation, which stimulated the expression of Jag-1 and Hes-1. Positive correlations were observed between the GNAQ and Jag-1 mRNA levels and between the GNAQ and Hes-1 mRNA levels. However, no positive correlation was observed between the GNAQ and YAP mRNA levels. The results suggested that GNAQ mutation induced viability and migration of uveal melanoma cells via Notch signaling activation, which is mediated by YAP dephosphorylation and nuclear translocation.
authors.affiliation: Department of Ophthalmology, Xi'an No. 4 Hospital, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Honglei
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Xi'an No. 4 Hospital, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Lei
authors.affiliation: Department of Ophthalmology, Xi'an No. 4 Hospital, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Keqin
authors.initials: K
authors.lastname: Long
authors.affiliation: Department of Ophthalmology, Xi'an No. 4 Hospital, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Xinguang
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, Xi'an No. 4 Hospital, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Zhaoliang
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Gerontology, Tangdu Hospital, Xi'an, Shaanxi 710038, P.R. China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Gerontology, Tangdu Hospital, Xi'an, Shaanxi 710038, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D051880:Receptors, Notch / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology; D000091102:YAP-Signaling Proteins; D000098943:Uveal Melanoma
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D051880:Receptors, Notch; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D043802:GTP-Binding Protein alpha Subunits, Gq-G11