The Epigenetic Role of MicroRNA’s in Retinoblastoma Proliferation and Invasion through Targeting of the Wnt/Beta-Catenin Pathway
Introduction. Retinoblastoma is the most frequently occurring pediatric ocular cancer.1 It arises from mutation in both alleles of the tumor suppressor gene Rb1 on chromosome 13, which codes for the cell cycle regulating retinoblastoma protein (pRb).2 Symptoms include leukocoria, vision loss, strabismus, and hypopyon.3 Early detection and treatment are associated with excellent prognosis, but retinoblastoma chemotherapeutic drugs have significant side effects for children.1 The Wnt/b-catenin signal transduction pathway is upregulated in retinoblastoma.4 The cytoplasmic protein b-catenin is degraded by b-catenin destruction complex, but binding of extracellular ligand Wnt to the Frizzled transmembrane receptor prevents association of the destruction complex, allowing b-catenin to translocate to the nucleus and turn on various proliferative genes.5 A variety of microRNA’s have been found to target the Wnt/b-catenin pathway in retinoblastoma. For instance, microRNA-485 inhibits Wnt signaling by directly binding Wnt3a and other genes of the Wnt gene family, resulting in decreased malignancy of retinoblastoma cells in vitro.6 MicroRNA-186 interacts with Disheveled-Axin Domain Containing 1 (DIXDC1), a protein encoding gene with increased expression in retinoblastoma cells; this interaction silences DIXDC1 and decreases Wnt signaling activity and retinoblastoma cell proliferation.7 MicroRNA-124 downregulates both the Wnt/b-catenin pathway and Slug pathway in retinoblastoma cells, leading to decreased cell proliferation and decreased loss of anchorage dependence, respectively.8 The findings of these in vitro studies are promising for potential treatment of retinoblastoma with microRNA. Methods. A promising 2019 study in a rat model showed microRNA therapy was effective against retinoblastoma cell proliferation. Melphalan is a chemotherapy drug used in retinoblastoma treatment, with toxic side effects. MicroRNA-181 regulates cancer progress through heightened expression of the pro-apoptotic BAX gene, which also has anti-Wnt signaling effects. Co-delivery of microRNA-181 and melphalan was attempted in the mouse model using 171 nm switchable lipid nanoparticles. An in-vivo xenograft retinoblastoma model in rats was used to observe effects of the therapy on retinoblastoma cell counts.9 Results. Co-delivery of melphalan with microRNA-181 significantly decreased retinoblastoma cell numbers in the rats compared to therapy with melphalan alone or microRNA-181 alone (p < 0.05). The results demonstrate that together, melphalan and the microRNA had synergistic effects in decreasing retinoblastoma cell survival and proliferation.9 Conclusions. These results are highly promising. If a lower dose of melphalan is needed due to microRNA complementarity, then toxic side effects of the drug can be mitigated. The study provides compelling in vivo evidence for the therapeutic potential of microRNA in retinoblastoma therapy.
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- Inhibition of Wnt/β-catenin by anthelmintic drug niclosamide effectively targets growth, survival, and angiogenesis of retinoblastoma. American Journal of Translational Research. 2017;9(8):3776-3786.
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- Lyu X, Wang L, Lu J, Zhang H, Wang L. MicroRNA‑485 inhibits the malignant behaviors of retinoblastoma by directly targeting Wnt3a. Oncology Reports. 2019;Epub ahead of print.
- Che X, Quian Y, Li D. Suppression of Disheveled-Axin Domain Containing 1 (DIXDC1) by MicroRNA-186 Inhibits the Proliferation and Invasion of Retinoblastoma Cells. Journal of Molecular Neuroscience. 2018;64(2):252-261.
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- Tabatabaei SN, Derbali RM, Yang C, Superstein R, Hamel P, Chain JL, Hardy P. Co-delivery of miR-181a and melphalan by lipid nanoparticles for treatment of seeded retinoblastoma. Journal of Controlled Release. 2019; 298:177-185