通过SREBP2抑制mir -181a驱动的胆固醇生物合成下调抑制葡萄膜黑色素瘤转移。

IF 12.8 1区 医学 Q1 ONCOLOGY
Rui Wang, Claudia Gilbert, Houda Tahiri, Chun Yang, Solange Landreville, Pierre Hardy
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引用次数: 0

摘要

背景:葡萄膜黑色素瘤(uveal melanoma, UM)是成人最常见的原发性眼内肿瘤,其转移是导致死亡的主要原因。然而,转移性UM的有效治疗仍然有限。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。方法:我们通过多个UM细胞系和脉络膜上注射小鼠模型研究miR-181a对UM转移的影响。进行功能分析,包括迁移、侵袭和癌症干细胞样细胞(CSC)的形成。通过生物信息学、荧光素酶测定和western blotting鉴定miR-181a的靶点。测量了胆固醇水平,体外和体内研究评估了miR-181a与克唑替尼联合的治疗潜力。结果:miR-181a显著降低UM细胞的迁移、侵袭和转移。在机制上,miR-181a被发现靶向固醇调节元件结合蛋白2 (SREBP2),从而抑制胆固醇的生物合成。这种胆固醇水平的降低阻碍了上皮细胞到间质转化(EMT)的减少,并导致肿瘤干细胞样细胞(CSC)数量的下降。此外,胆固醇升高或SREBP2过表达会取消miR-181a的抗转移作用。此外,miR-181a和克唑替尼联合使用在体内和体外都能显著抑制转移。结论:miR-181a通过靶向SREBP2和降低胆固醇生物合成来抑制UM转移。它与克唑替尼联合可能为转移性UM提供一种有希望的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
MiR-181a-driven downregulation of cholesterol biosynthesis through SREBP2 inhibition suppresses uveal melanoma metastasis.

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.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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