2. Academic Validation
  3. MiR-181a-driven downregulation of cholesterol biosynthesis through SREBP2 inhibition suppresses uveal melanoma metastasis

MiR-181a-driven downregulation of cholesterol biosynthesis through SREBP2 inhibition suppresses uveal melanoma metastasis

  • J Exp Clin Cancer Res. 2025 Jul 19;44(1):215. doi: 10.1186/s13046-025-03459-8.
Rui Wang 1,  Claudia Gilbert 2,  Houda Tahiri 2,  Chun Yang 2,  Solange Landreville 3 4 5 6,  Pierre Hardy 7 8 9
Affiliations

Affiliations

  • 1 Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC, H3T 1C5, Canada.
  • 2 Research Center of CHU Sainte-Justine, Université de Montréal, Montréal, QC, H3T 1C5, Canada.
  • 3 Department of Ophthalmology and Otorhinolaryngology-Cervico-Facial Surgery, Faculty of Medicine, Université Laval, Quebec City, QC, G1V 0A6, Canada.
  • 4 Hôpital du Saint-Sacrement, Regenerative Medicine Division, CHU de Québec-Université Laval Research Centre, Quebec City, QC, G1S 4L8, Canada.
  • 5 Université Laval Cancer Research Center, Quebec City, QC, G1R 3S3, Canada.
  • 6 Centre de Recherche en Organogénèse Expérimentale de l'Université Laval/LOEX, Quebec City, QC, G1J 1Z4, Canada.
  • 7 Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC, H3T 1C5, Canada. pierre.hardy.med@ssss.gouv.qc.ca.
  • 8 Research Center of CHU Sainte-Justine, Université de Montréal, Montréal, QC, H3T 1C5, Canada. pierre.hardy.med@ssss.gouv.qc.ca.
  • 9 Department of Pediatrics, Université de Montréal, Montréal, QC, H3T 1C5, Canada. pierre.hardy.med@ssss.gouv.qc.ca.
PMID: 40684202 DOI: 10.1186/s13046-025-03459-8
Abstract

Background: uveal melanoma (UM) is the most common primary intraocular tumor in adults, with metastasis being the leading cause of death. However, effective treatments for metastatic UM remain limited. Emerging evidence suggests that Cholesterol metabolism plays a role in Cancer progression, but its impact on UM metastasis is not well understood.

Methods: we investigated the effects of miR-181a on UM metastasis using multiple UM cell lines and a suprachoroidal injection mouse model. Functional assays, including migration, invasion, and Cancer stem-like cell (CSC) formation, were performed. The target of miR-181a was identified through bioinformatics, luciferase assays, and western blotting. Cholesterol levels were measured, and in vitro and in vivo studies assessed the therapeutic potential of combining miR-181a with crizotinib.

Results: miR-181a significantly decreases UM cell migration, invasion, and metastasis. Mechanistically, miR-181a was found to target sterol regulatory element-binding protein 2 (SREBP2), thereby inhibiting Cholesterol biosynthesis. This decrease in Cholesterol levels hindered reduced epithelial-to-mesenchymal transition (EMT) and led to a decline in Cancer stem-like cell (CSC) populations in UM. Furthermore, elevated Cholesterol or overexpression of SREBP2 abrogated the anti-metastatic effects of miR-181a. Additionally, a combination of miR-181a and crizotinib significantly inhibited metastasis, both in vitro and in vivo.

Conclusions: miR-181a inhibits UM metastasis by targeting SREBP2 and reducing Cholesterol biosynthesis. Its combination with crizotinib may provide a promising therapeutic strategy for metastatic UM.

Keywords

Cholesterol biosynthesis; Combinational therapy; Crizotinib; Metastasis; SREBP2; Uveal melanoma; miR-181a.

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