MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer.
MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer.
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DOI：
10.15252/emmm.202216033
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发表时间：
2023-01-11
影响因子：
11.1
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中科院分区：
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端粒重复序列结合因子2（TRF 2）是一种端粒加帽蛋白，在维持端粒结构和功能中起关键作用。它在不同的癌症类型中高度表达，并有助于癌症进展。迄今为止，靶向TRF 2的抗癌策略仍然是一个挑战。在这里，我们开发了一种基于miRNA的方法来减少TRF 2的表达。通过对54种候选miRNAs进行高通量荧光素酶筛选，我们将miR-182 - 3 p鉴定为TRF 2的特异性和有效的转录后调节因子。miR-182 - 3 p的异位表达显著降低了一组端粒酶或端粒替代延长（ALT）阳性癌细胞系中的TRF 2蛋白水平。此外，miR-182 - 3 p在端粒和近着丝粒位点诱导DNA损伤，最终导致强烈的凋亡激活。我们还观察到，用含有miR-182 - 3 p的脂质纳米颗粒（LNP）治疗损害了三阴性乳腺癌（TNBC）模型中的肿瘤生长，包括患者来源的肿瘤异种移植物（PDTX），而不影响小鼠存活或组织功能。最后，LNPs-miR-182 - 3 p能够穿过血脑屏障并减少颅内肿瘤，这代表了转移性脑病变的可能治疗选择。开发了一种基于miRNA的抑制端粒蛋白TRF 2的策略，这导致了三阴性乳腺癌生长的有效减少。
The telomeric repeat‐binding factor 2 (TRF2) is a telomere‐capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti‐cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA‐based approach to reduce TRF2 expression. By performing a high‐throughput luciferase screening of 54 candidate miRNAs, we identified miR‐182‐3p as a specific and efficient post‐transcriptional regulator of TRF2. Ectopic expression of miR‐182‐3p drastically reduced TRF2 protein levels in a panel of telomerase‐ or alternative lengthening of telomeres (ALT)‐positive cancer cell lines. Moreover, miR‐182‐3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR‐182‐3p impaired tumor growth in triple‐negative breast cancer (TNBC) models, including patient‐derived tumor xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs‐miR‐182‐3p were able to cross the blood–brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions. A miRNA‐based strategy to inhibit the telomeric protein TRF2 was developed, which led to efficient decrease of triple negative breast cancer growth.