Department of Ophthalmology, The First Hospital of China Medical University, No. 155, Nanjing Bei Street, Heping District, Shenyang, 110001, Liaoning Province, China.
The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning Province, China.
Mol Cell Biochem. 2018 Aug;445(1-2):25-33. doi: 10.1007/s11010-017-3248-x. Epub 2017 Dec 19.
Choroidal melanoma is the most common intraocular tumor in adults, and overexpression of matrix metalloproteinase-2 or matrix metalloproteinase-9 (MMP-2/MMP-9) is associated with angiogenesis and tumor metastasis of the choroidal malignant melanoma (CMM). This study aims to investigate the functions and mechanisms of microRNA or long non-coding RNA-targeted MMP-2/MMP-9 in CMM. We demonstrated that expressions of MMP-2/MMP-9 were increased in CMM tissues and C918 cells in comparison with normal choroidal melanocytes. Bio-informatics prediction and our experiments validated that MMP-2 and MMP-9 were simultaneously targeted by miR-296-3p and FOXC1 promoter upstream transcript (FOXCUT); the latter two exerted tumor-suppressing effects on CMM cells by inhibiting cell proliferation, cell cycle progression, migration, invasion, and induction of cell apoptosis. Furthermore, significant downregulations of miR-296-3p and FOXCUT were found in C918 cells compared with choroidal melanocytes from the unaffected eyes, and a positive correlation was observed between their levels in three cases of eye malignant melanomas. Our data indicated that MMP-2/MMP-9 was coordinately targeted by two non-coding RNAs, miR-296-3p and FOXCUT, which were decreased, and tumor-suppressing factors in CMM. Further study will show the possibility of developing them as therapeutic candidates for CMM.
脉络膜黑色素瘤是成年人中最常见的眼内肿瘤，基质金属蛋白酶-2 或基质金属蛋白酶-9（MMP-2/MMP-9）的过表达与脉络膜恶性黑色素瘤（CMM）的血管生成和肿瘤转移有关。本研究旨在探讨 microRNA 或长非编码 RNA 靶向 MMP-2/MMP-9 在 CMM 中的作用和机制。我们证实 MMP-2/MMP-9 的表达在 CMM 组织和 C918 细胞中高于正常脉络膜黑素细胞。生物信息学预测和我们的实验验证了 MMP-2 和 MMP-9 同时受到 miR-296-3p 和 FOXC1 启动子上游转录物（FOXCUT）的靶向调控；后两者通过抑制细胞增殖、细胞周期进程、迁移、侵袭和诱导细胞凋亡对 CMM 细胞发挥肿瘤抑制作用。此外，与未受影响眼的脉络膜黑素细胞相比，C918 细胞中的 miR-296-3p 和 FOXCUT 明显下调，三例眼恶性黑色素瘤中它们的水平呈正相关。我们的数据表明，MMP-2/MMP-9 被两个非编码 RNA（miR-296-3p 和 FOXCUT）共同靶向，这些非编码 RNA 下调，是 CMM 中的肿瘤抑制因子。进一步的研究将显示它们作为 CMM 治疗候选物的可能性。
