Abstract
Simple SummaryHuman uveal melanoma (UM) is the most common primary intraocular tumor with high metastatic risk in adults. Currently, no effective treatment is available for metastatic UM; therefore, new therapeutic approaches are needed to improve overall survival. Given the increased understanding of microRNAs (miRNAs) and their roles in UM tumorigenesis and metastasis, miRNA-based therapy may offer the hope of improving therapeutic outcomes. This review summarizes the actions of select miRNAs examined in preclinical studies using miRNAs as therapeutic targets in UM. The focus of this review is the application of established nanotechnology-assisted delivery systems to overcome the limitations of therapeutic miRNAs. A blend of therapeutic miRNAs and nanodelivery systems may facilitate the translation of miRNA therapies to clinical settings.Uveal melanoma (UM) is the most common adult intraocular cancer, and metastatic UM remains deadly and incurable. UM is a complex disease associated with the deregulation of numerous genes and redundant intracellular signaling pathways. As understanding of epigenetic dysregulation in the oncogenesis of UM has increased, the abnormal expression of microRNAs (miRNAs) has been found to be an epigenetic mechanism underlying UM tumorigenesis. A growing number of miRNAs are being found to be associated with aberrant signaling pathways in UM, and some have been investigated and functionally characterized in preclinical settings. This review summarizes the miRNAs with promising therapeutic potential for UM treatment, paying special attention to the therapeutic miRNAs (miRNA mimics or inhibitors) used to restore dysregulated miRNAs to their normal levels. However, several physical and physiological limitations associated with therapeutic miRNAs have prevented their translation to cancer therapeutics. With the advent of nanotechnology delivery systems, the development of effective targeted therapies for patients with UM has received great attention. Therefore, this review provides an overview of the use of nanotechnology drug delivery systems, particularly nanocarriers that can be loaded with therapeutic miRNAs for effective delivery into target cells. The development of miRNA-based therapeutics with nanotechnology-based delivery systems may overcome the barriers of therapeutic miRNAs, thereby enabling their translation to therapeutics, enabling more effective targeting of UM cells and consequently improving therapeutic outcomes.
Highlights
Uveal melanoma (UM) is the most common adult intraocular malignment tumor arising from melanocytes in the uveal tract, including the iris, ciliary body and choroid
Genetic analysis has indicated that UM metastasis and shorter survival is associated with the loss of a copy of chromosome 3 and germline mutations of the tumor suppressor gene BRCA-associated protein 1 (BAP1)
With the increased knowledge regarding the dysregulation of miRNAs that underlie the oncogenesis of UM, preclinical studies of specific UM therapies are increasingly being reported
Summary
Uveal melanoma (UM) is the most common adult intraocular malignment tumor arising from melanocytes in the uveal tract, including the iris, ciliary body and choroid. The anti-UM properties of several tumor suppressor miRNAs have been investigated in functional studies and have shown strong inhibition of UM cell proliferation, migration and invasion, as well as in vivo tumor growth repression. MiR-142-3p directly targets several genes associated with GNAQ/11 and downstream signaling pathways, including GNAQ, RAC1, transforming growth factor beta receptor 1 (TGFβR1), cell division cycle 25C (CDC25C) and Wiskott–Aldrich syndrome protein (WASL) [48]. MiR-145 directly targets oncogene insulin receptor substrate-1 (IRS-1) and neuroblastoma RAS viral oncogene homolog (N-RAS) and VEGF, significantly suppressing UM cell invasion, angiogenesis and tumor growth [62,63]. MiR-182 targets multiple oncogenic genes, including microphthalmia-associated transcription factor (MITF), cyclin D2 and pro-apoptotic B-cell lymphoma 2 (BCL2) [64]. The tumor suppressor role of miR-181a in retinoblastoma has been demonstrated in our previous studies [67]
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