Wang Rui, Gilbert Claudia, Tahiri Houda, Yang Chun, Landreville Solange, Hardy Pierre
Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC, H3T 1C5, Canada.
Research Center of CHU Sainte-Justine, Université de Montréal, Montréal, QC, H3T 1C5, Canada.
J Exp Clin Cancer Res. 2025 Jul 19;44(1):215. doi: 10.1186/s13046-025-03459-8.
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.
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.
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.
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.
葡萄膜黑色素瘤（UM）是成人中最常见的原发性眼内肿瘤，转移是主要的死亡原因。然而，针对转移性UM的有效治疗方法仍然有限。新出现的证据表明胆固醇代谢在癌症进展中起作用，但其对UM转移的影响尚不清楚。
我们使用多种UM细胞系和脉络膜上腔注射小鼠模型研究了miR-181a对UM转移的影响。进行了包括迁移、侵袭和癌干细胞样细胞（CSC）形成在内的功能测定。通过生物信息学、荧光素酶测定和蛋白质印迹法鉴定了miR-181a的靶标。测量了胆固醇水平，并通过体外和体内研究评估了miR-181a与克唑替尼联合使用的治疗潜力。
miR-181a显著降低UM细胞的迁移、侵袭和转移。机制上，发现miR-181a靶向固醇调节元件结合蛋白2（SREBP2），从而抑制胆固醇生物合成。胆固醇水平的降低阻碍了上皮-间质转化（EMT）的减少，并导致UM中癌干细胞样细胞（CSC）群体的减少。此外，胆固醇升高或SREBP2过表达消除了miR-181a的抗转移作用。此外，miR-181a与克唑替尼联合使用在体外和体内均显著抑制转移。
miR-181a通过靶向SREBP2和减少胆固醇生物合成来抑制UM转移。它与克唑替尼联合使用可能为转移性UM提供一种有前景的治疗策略。
