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Overexpression of microRNA-130a represses uveal melanoma cell migration and invasion through inactivation of the Wnt/β-catenin signaling pathway by downregulating USP6

Cancer Gene Therapy volume 29, pages 930–939 (2022)Cite this article

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Abstract

Uveal melanoma (UM) is a neoplasm arising from melanocytes of the ciliary body, choroid, and iris of the eye, which is the most common primary malignant intraocular tumor. microRNA-130a (miR-130a) has been confirmed to be underexpressed in many types of cancers. Here we aimed to investigate the mechanism whereby miR-130a affects the Wnt/β-catenin signaling pathway by targeting ubiquitin-specific protease 6 (USP6) in UM. Ocular specimens of 62 patients with UM and 42 participants subjected to enucleation due to trauma were collected. In the normal uveal tissues and those from metastatic and non-metastatic UM, we evaluated miR-130a expression by RT-qPCR and then measured mRNA and protein expression of recombinant human mothers against decapentaplegic homolog 4 (SMAD4), USP6, related factors of the Wnt/β-catenin signaling pathway, and epidermal growth factor receptor (EGFR) by RT-qPCR and western blot analysis. Subsequently, the interaction between miR-130a and USP6 was identified by bioinformatics analysis and dual-luciferase reporter gene assay. Next, UM cell migration and invasion abilities, as well as tumor growth in nude mice, were measured through gain- and loss-of-function studies of miR-130a and USP6. miR-130a expression was downregulated in uveal tissues from patients with UM, especially in metastatic uveal tissues. The overall survival of UM patients with low miR-130a expression was shorter than those with high miR-130a expression. USP6 was a target of miR-130a and the overexpression of miR-130a or inhibition of USP6 in UM MUM-2B and MUM-2C cell lines inhibited the expression of Wnt, β-catenin, and EGFR, and activated SMAD4 expression, while reducing UM cell migration and invasion abilities in vitro. The above changes could be reversed by overexpressing USP6 in vitro, whereas overexpressed miR-130a could inhibit the tumor growth in nude mice. Taken together, overexpressed miR-130a inhibited USP6 expression to repress UM cell migration and invasion abilities through inactivating the Wnt/β-catenin signaling pathway, which could be a potential candidate for treatment of UM.

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Fig. 1: Bioinformatics analysis of the differentially expressed genes and their molecular interactions in UM.
Fig. 2: High miR-130a expression predicts a good prognosis for survival of UM patients.
Fig. 3: Upregulated miR-130a reduces cell migration and invasion in UM MUM-2B and MUM-2C cell lines.
Fig. 4: USP6 is a target of miR-130a.
Fig. 5: Silencing USP6 impedes cell migration and invasion via inactivation of the Wnt/β-catenin signaling pathway in UM MUM-2B and MUM-2C cell lines.
Fig. 6: USP6 mediates the influence of miR-130a on UM MUM-2B and MUM-2C cell migration and invasion abilities.
Fig. 7: miR-130 overexpression delays tumor growth of nude mice.

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Authors and Affiliations

  1. Department of Orbital Disease and Ocular Plastic Surgery, The Second Hospital of Jilin University, Changchun, China

    Shuai Wu

  2. Department of Strabismus and Pediatric Ophthalmology, The Second Hospital of Jilin University, Changchun, China

    Mei Han & Chao Zhang

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Correspondence to Chao Zhang.

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Wu, S., Han, M. & Zhang, C. Overexpression of microRNA-130a represses uveal melanoma cell migration and invasion through inactivation of the Wnt/β-catenin signaling pathway by downregulating USP6. Cancer Gene Ther 29, 930–939 (2022). https://doi.org/10.1038/s41417-021-00377-7

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