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miR-142-3p suppresses uveal melanoma by targeting CDC25C, TGFβR1, GNAQ, WASL, and RAC1

Authors Peng D, Dong J, Zhao Y, Peng X, Tang J, Chen X, Wang L, Hu DN, Reinach PS, Qu J, Yan D

Received 22 February 2019

Accepted for publication 18 April 2019

Published 24 May 2019 Volume 2019:11 Pages 4729—4742

DOI https://doi.org/10.2147/CMAR.S206461

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo


Dewei Peng,1,2 Jing Dong,1,2 Yunping Zhao,1,2 Xiaomei Peng,1,2 Jingjing Tang,1,2 Xiaoyan Chen,1,2 Lihua Wang,1,2 Dan-Ning Hu,2,3 Peter S Reinach,1,2 Jia Qu,1,2 Dongsheng Yan1,2

1School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, Zhejiang, People’s Republic of China; 3Tissue Culture Center, New York Eye and Ear Infirmary, New York Medical College, New York, NY, USA

Purpose: Uveal melanoma (UM) is the most frequent metastatic ocular tumor in adults. Therapeutic intervention remains ineffective since none of the novel procedures used to treat this disease increased survival rates. To deal with this limitation, additional studies are required to clarify its pathogenesis. The current study focused on describing how epigenetic modulation by miR-142-3p affects changes in some cellular functions underlying UM pathogenesis.
Methods and results: Microarray analysis identified 374 miRNAs which were differentially expressed between UM cells and uveal melanocytes. miR-142-3p was one of the 10 most downregulated miRNAs. Quantitative RT-PCR analysis confirmed that miR-142-3p expression levels were significantly decreased in both UM cell lines and clinical specimens. The results of the MTS, clone formation, scratch wound, transwell assays, and in vivo biofluorescence imaging showed that miR-142-3p overexpression significantly inhibited cell proliferation, migration, and invasiveness. Nevertheless, miR-142-3p did not affect cell apoptotic activity or sensitivity to doxorubicin. Cell cycle and EdU analysis showed that miR-142-3p overexpression induced G1/G2 cell cycle arrest and reduced DNA synthesis in UM cells. Microarray analysis showed that miR-142-3p mainly regulates the TGFβ signaling pathway, and those in which MAPK and PI3K-Akt are constituents. Functional interactions between miR-142-3p and CDC25C, TGFβR1, GNAQ, WASL, and RAC1 target genes were confirmed based on the results of the luciferase reporter assay and Western blot analysis. CDC25C or RAC1 downregulation is in agreement with cell cycle arrest and DNA synthesis disorder induction, while downregulation of TGFβR1, GNAQ, WASL, or RAC1 accounts for declines in cell migration.
Conclusion: miR-143-3p is a potential therapeutic target to treat UM since overriding its declines in expression that occur in this disease reversed the pathogenesis of this disease. Such insight reveals novel biomarker for decreasing UM vitality and for improved tracking of tumor progression.

Keywords: miR-142-3p, uveal melanoma, tumor suppressor, molecular mechanisms

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