期刊
JOURNAL OF CELLULAR BIOCHEMISTRY
卷 120, 期 4, 页码 5766-5776出版社
WILEY
DOI: 10.1002/jcb.27863
关键词
G protein subunit alpha q (GNAQ); H101; melanoma; uveal melanoma; Yes-associated protein (YAP) pathway
资金
- Science and Technology Commission of Shanghai [17DZ2260100]
- National Natural Science Foundation of China [81372469, 81570884, 81772875, 81770961]
- Scientific Research Program of the National Health and Family Planning Commission of China [201402014]
- SMC-ChenXing Yong Scholar Program
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine [20152223]
Background Uveal melanoma (UM) is a severe human malignancy with a high mortality rate, as well as high metastasis and recurrence potential. The active mutation of G protein subunit alpha q (GNAQ) or G protein subunit alpha 11 (GNA11) is a major trigger for UM. Oncolytic adenovirus H101 (H101) is the first oncolytic virus approved for clinical applications in cancer therapy by the China Food and Drug Administration. We investigated whether combining H101 with the downregulation of GNAQ expression would act synergistically in UM therapy. Methods Three UM cell lines OMM2.3 and 92.1, harboring GNAQ mutation, and OCM1, harboring B-Raf proto-oncogene mutation, were chosen for our research. The cellular toxicity of adenoviral infection and the cell growth rate were measured with a Cell Counting Kit-8. Western blot analysis was used to detect GNAQ, p-MEK1/2, YAP, and p-YAP expression. The apoptosis and cell-cycle distribution of cells were evaluated with annexin-V and propidium iodide staining. Results Our results revealed that OMM2.3 and 92.1 cells were more sensitive to H101 infection than OCM1 cells. GNAQ expression was markedly reduced by small interfering RNA, siGNAQ. Combined treatment of siGNAQ and H101 inhibited the proliferation and activated the apoptosis of OMM2.3 and 92.1 cells by blocking the phosphorylation of MEK1/2 and increasing the phosphorylation of YAP. Conclusions In summary, a therapy combining H101 and siGNAQ is feasible, with potential utility as a novel targeted molecular therapy for UM, especially those carrying a GNAQ mutation.
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