Long Noncoding RNA PVT1 Silencing Prevents the Development of Uveal Melanoma by Impairing MicroRNA-17-3p–Dependent MDM2 Upregulation

Abstract

PURPOSE. Uveal melanoma is a common primary intraocular malignancy accompanied by high mortality. Previous evidence has highlighted the implication of microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in uveal melanoma. Accordingly, we further uncovered the possible role of lncRNA plasmacytoma variant translocation 1 gene (PVT1) and microRNA-17-3p (miR-17-3p) in uveal melanoma. METHODS. A series of experiments were performed to examine the relationship among lncRNA PVT1, miR-17-3p, and murine double minute clone 2 oncoprotein (MDM2). Afterward, gain-and loss-of-function approaches were used with uveal melanoma cells to verify the role of lncRNA PVT1, miR-17-3p, and MDM2 in the tumorigenesis and development of uveal melanoma. RESULTS. Highly expressed lncRNA PVT1 and MDM2, yet lowly expressed miR-17-3p, were identified in ocular uveal melanoma tissues versus normal adjacent tissues. Then, dual luciferase reporter gene assay, RNA binding protein immunoprecipitation, and RNA pull-down assays showed that lncRNA PVT1 specifically bound to miR-17-3p, and that MDM2 was a target gene of miR-17-3p. Gain-and loss-of-function studies elucidated that silencing of lncRNA PVT1 or overexpression of miR-17-3p resulted in decreased MDM2 expression and increased transcriptional activity of p53, in addition to inhibiting uveal melanoma cell proliferation, migration, and invasion, yet promoted cell apoptosis in vitro. In addition, lncRNA PVT1 silencing or miR-17-3p overexpression was noted to inhibit tumor growth in vivo. CONCLUSIONS. Downregulation of lncRNA PVT1 could potentially promote miR-17-3p expression to suppress tumorigenesis and development of uveal melanoma by activating the p53 signaling pathway through binding to MDM2.

Liquid Biopsy for Solid Ophthalmic Malignancies: An Updated Review and Perspectives

“…Several in vitro studies demonstrated that lncRNAs played a role in UM tumorigenesis. The lncRNA PVT1 (Plasmacytoma variant translocation 1 gene) was found to be overexpressed in tissue biopsy of 28 UM patients [71]. This finding was consistent with those of Xu et al, who investigated the expression of lncRNA PVT1 by using deep-RNA sequencing data from the UM Cancer Genome Atlas.…”

<p>LncRNA PVT1 Suppresses the Progression of Renal Fibrosis via Inactivation of TGF-β Signaling Pathway</p>

“…[36][37][38] Wu et al indicated that PVT1 silencing could prevent the development of uveal melanoma through impairing miR-17-3p-dependent MDM2 upregulation. 39 Furthermore, PVT1 could modulate the proliferation and apoptosis of lens epithelial cells in diabetic cataract through regulation miR-214-3p/MMP2 axis. 30 Besides, it has been previously reported that miR-181a-5p could mediate the progression of renal fibrosis.…”

The Role of Non-Coding RNAs in Uveal Melanoma

“…The levels of lncRNA PVT1 (Chr 8q24.21) were found to be considerably higher in UM compared to normal tissues [ 21 , 90 ]. It has an oncogenic function in the initiation and development of metastasis of various neoplasms, including UM [ 96 , 97 , 98 , 99 ].…”

“…It has an oncogenic function in the initiation and development of metastasis of various neoplasms, including UM [ 96 , 97 , 98 , 99 ]. The silencing of PVT1 impedes the biological functions of UM cells, resulting in the inhibition of proliferation, S-phase sequestration, and migration in addition to inducing apoptosis [ 21 ].…”

“…The mechanisms by which PVT1 exerts its carcinogenic function in UM are through the positive regulation of EZH2 expression [ 90 ] as well as its function in regulating the miR-17-3p/MDM2/p53 axis. Wu et al [ 21 ] showed that there is specific binding between lncRNA PVT1 and miR-17-3p, which implies inhibition of the expression of this microRNA. In addition, they demonstrated low expression of miR-17-3p and a high level of MDM2 in UM tissues, with a targeting relationship between both.…”