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Updated: Aug 10, 2025
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
MiR-181a-5p inhibits uveal melanoma development by targeting GNAQ and AKT3
Rui Wang1, Houda Tahiri2, Chun Yang2
1Department of Pharmacology and Physiology, Université de Montréal Montréal, QC H3T 1C5, Canada.
Abstract:
Uveal melanoma (UM) is the most common primary intraocular malignant tumor type in adults. Even after the treatment of the ocular tumor, the prognosis of patients with metastasis remains poor. Hence, an urgent unmet need exists to identify novel approaches to treat advanced UM. Previous studies have revealed G subunit alpha Q and alpha 11 (GNAQ/11) mutations in more than 85% of patients with UM, thus indicating the importance of GNAQ and downstream signaling pathways in UM occurrence. Here, we demonstrate that microRNA (miR)-181a-5p, a small non-coding RNA, effectively inhibited the viability, proliferation, and colony formation but induced apoptosis of UM cells. Furthermore, silencing GNAQ or AKT3 mimicked the anti-UM effects of miR-181a-5p, whereas overexpression of GNAQ or AKT3 rescued the anti-UM effects induced by miR-181a-5p. In addition, miR-181a-5p had a stronger effect in decreasing the viability of GNAQ mutant than GNAQ wild-type cells. Moreover, miR-181a-5p suppressed the total expression and phosphorylation of members of the ERK and PI3K/AKT/mTOR signaling pathways. Importantly, miR-181a-5p potently inhibited the growth of UM xenografts in nude mice. MiR-181a-5p also decreased the expression of Ki67, GNAQ, and AKT3, and induced the expression of cleaved-caspase3 in UM tumors. These results suggest that miR-181a-5p inhibits UM development by targeting GNAQ and AKT3.
Insights
MicroRNA-181a-5p effectively targets GNAQ and AKT3, inhibiting uveal melanoma (UM) cell growth and tumor development. This finding offers a promising new therapeutic strategy for advanced UM patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Uveal melanoma (UM) is the most common adult intraocular malignancy with poor prognosis post-metastasis.
- GNAQ/11 mutations are prevalent in over 85% of UM cases, highlighting their critical role in tumor development.
- Novel therapeutic strategies are urgently needed for advanced UM.
Purpose of the Study:
- To investigate the therapeutic potential of microRNA (miR)-181a-5p in treating uveal melanoma.
- To elucidate the molecular mechanisms underlying miR-181a-5p's anti-UM effects, focusing on GNAQ and downstream pathways.
Main Methods:
- In vitro studies assessing UM cell viability, proliferation, apoptosis, and colony formation.
- In vivo xenograft models in nude mice to evaluate tumor growth inhibition.
- Analysis of signaling pathways including ERK and PI3K/AKT/mTOR, and protein expression (Ki67, GNAQ, AKT3, cleaved-caspase3).
Main Results:
- MiR-181a-5p significantly inhibited UM cell viability, proliferation, and colony formation, while inducing apoptosis.
- Silencing GNAQ or AKT3 mimicked miR-181a-5p's effects; their overexpression rescued these effects.
- MiR-181a-5p suppressed ERK and PI3K/AKT/mTOR signaling pathways and inhibited UM xenograft growth in vivo.
- Downregulation of Ki67, GNAQ, and AKT3, and upregulation of cleaved-caspase3 were observed in treated tumors.
Conclusions:
- MiR-181a-5p demonstrates potent anti-tumor activity against uveal melanoma.
- The therapeutic effects of miR-181a-5p are mediated through the targeting of GNAQ and AKT3, impacting key oncogenic signaling pathways.
- MiR-181a-5p represents a promising therapeutic candidate for advanced uveal melanoma.
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