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局部 microRNA 递送靶向 Palladin 并预防转移性乳腺癌。

Local microRNA delivery targets Palladin and prevents metastatic breast cancer.

机构信息

Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.

Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Cambridge, Massachusetts 02139, USA.

出版信息

Nat Commun. 2016 Sep 19;7:12868. doi: 10.1038/ncomms12868.

DOI:10.1038/ncomms12868
PMID:27641360
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5031803/
Abstract

Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3'-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug.

摘要

转移是乳腺癌患者死亡的主要原因。microRNAs 作为基因表达的主要调控因子，是控制转移的有吸引力的候选物。在这里，我们表明 miR-96 或 miR-182 的治疗可以预防乳腺癌转移，并阐明其作用机制。我们发现 miR-96/miR-182 下调 Palladin 蛋白水平，从而降低乳腺癌细胞的迁移和侵袭。Palladin 3'UTR 内 miR-96/miR-182 结合位点的常见 SNP(rs1071738) 消除了 miRNA:mRNA 的结合，从而减少了这些 miRNA 对 Palladin 的调控。通过应用互补 miRNA 可以成功恢复调控。一种水凝胶嵌入的、基于金纳米颗粒的递药载体提供了有效的局部、选择性和持续释放 miR-96/miR-182，显著抑制了乳腺癌小鼠模型中的转移。将 miRNA 与化疗药物顺铂联合递送，可显著缩小原发性肿瘤并预防转移。我们的数据证实了 miRNA 在转移中的作用，并表明 miR-96/miR-182 的递药具有作为一种潜在的抗转移药物的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/a993d17ffd29/ncomms12868-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/a008c35f7f5e/ncomms12868-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/1de2c946b88b/ncomms12868-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/1bc01533512b/ncomms12868-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/644ee6b32d42/ncomms12868-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/9914c19d2d08/ncomms12868-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/193bd827df07/ncomms12868-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/a993d17ffd29/ncomms12868-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/a008c35f7f5e/ncomms12868-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/1de2c946b88b/ncomms12868-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/1bc01533512b/ncomms12868-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/644ee6b32d42/ncomms12868-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/9914c19d2d08/ncomms12868-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/193bd827df07/ncomms12868-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6f0/5031803/a993d17ffd29/ncomms12868-f7.jpg

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本文引用的文献

[1]
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Nat Mater. 2016-3

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