Bioengineered miR-124-3p prodrug selectively alters the proteome of human carcinoma cells to control multiple cellular components and lung metastasis in vivo.
Bioengineered miR-124-3p prodrug selectively alters the proteome of human carcinoma cells to control multiple cellular components and lung metastasis in vivo.
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DOI：
10.1016/j.apsb.2021.07.027
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Yu AM
中科院分区：
文献类型：
--
作者：
Deng L;Petrek H;Tu MJ;Batra N;Yu AX;Yu AM
随着对microRNA（miRNA或miR）在肿瘤发生、进展和转移中的功能的理解，正在努力开发新的基于miRNA的疗法。最近，我们证明了一种新的人源化生物工程miR-124- 3 p前药在小鼠模型中控制自发性肺转移的有效性。本研究旨在探讨miR-124- 3 p调控肿瘤转移的分子和细胞机制。蛋白质组学研究鉴定了一组在A549细胞中被生物工程miR-124- 3 p选择性且显著下调的蛋白质，这些蛋白质被组装成对转移潜力至关重要的多个细胞组分。其中，plectin（PLEC）被证实是连接细胞骨架组分和连接点的miR-124- 3 p的新的直接靶点。在经miR-124- 3 p处理的肺癌和骨肉瘤细胞中，波形蛋白、talin 1（TLN 1）、整合素β-1（ITGB 1）、含IQ基序的GTP活化蛋白1（IQGAP 1）、钙粘蛋白2或N-钙粘蛋白（CDH 2）和连接粘附分子A（F11 R或JAMA或JAM 1）的蛋白水平降低，导致细胞骨架重塑和细胞-细胞连接破坏。此外，miR-124- 3 p显著抑制粘着斑的形成，导致细胞粘附能力降低。此外，在体内侵袭性实验转移小鼠模型中确立了生物miR-124- 3 p疗法的功效和安全性。这些结果将miR-124- 3 p-PLEC信号传导与控制细胞骨架、细胞连接和粘附的其他元件联系起来，这些元件对于癌细胞侵袭和向转移外渗至关重要，并支持miR-124治疗的前景。生物工程改造的miR-124- 3 p的抗转移活性可归因于作为多种细胞组分基础的蛋白质的选择性下调，所述细胞组分包括细胞骨架、细胞连接和粘着斑，其对于侵袭和外渗至关重要。
With the understanding of microRNA (miRNA or miR) functions in tumor initiation, progression, and metastasis, efforts are underway to develop new miRNA-based therapies. Very recently, we demonstrated effectiveness of a novel humanized bioengineered miR-124-3p prodrug in controlling spontaneous lung metastasis in mouse models. This study was to investigate the molecular and cellular mechanisms by which miR-124-3p controls tumor metastasis. Proteomics study identified a set of proteins selectively and significantly downregulated by bioengineered miR-124-3p in A549 cells, which were assembled into multiple cellular components critical for metastatic potential. Among them, plectin (PLEC) was verified as a new direct target for miR-124-3p that links cytoskeleton components and junctions. In miR-124-3p-treated lung cancer and osteosarcoma cells, protein levels of vimentin, talin 1 (TLN1), integrin beta-1 (ITGB1), IQ motif containing GTPase activating protein 1 (IQGAP1), cadherin 2 or N-cadherin (CDH2), and junctional adhesion molecule A (F11R or JAMA or JAM1) decreased, causing remodeling of cytoskeletons and disruption of cell–cell junctions. Furthermore, miR-124-3p sharply suppressed the formation of focal adhesion plaques, leading to reduced cell adhesion capacity. Additionally, efficacy and safety of biologic miR-124-3p therapy was established in an aggressive experimental metastasis mouse model in vivo. These results connect miR-124-3p−PLEC signaling to other elements in the control of cytoskeleton, cell junctions, and adhesion essential for cancer cell invasion and extravasation towards metastasis, and support the promise of miR-124 therapy. The antimetastatic activity of bioengineered miR-124-3p is attributable to selective downregulation of proteins underlying multiple cellular components, including cytoskeleton, cell junctions, and focal adhesion, critical for invasion and extravasation.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
DOI：
10.1016/j.apsb.2016.02.001
发表时间：
2016-07
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Ha D;Yang N;Nadithe V
通讯作者：
Nadithe V
影响因子：
11.2
作者：
Bader AG;Brown D;Winkler M
通讯作者：
Winkler M
影响因子：
64.5
作者：
Hatziapostolou M;Polytarchou C;Aggelidou E;Drakaki A;Poultsides GA;Jaeger SA;Ogata H;Karin M;Struhl K;Hadzopoulou-Cladaras M;Iliopoulos D
通讯作者：
Iliopoulos D
DOI：
10.1016/j.apsb.2020.10.005
发表时间：
2020-11
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Charbe NB;Amnerkar ND;Ramesh B;Tambuwala MM;Bakshi HA;Aljabali AAA;Khadse SC;Satheeshkumar R;Satija S;Metha M;Chellappan DK;Shrivastava G;Gupta G;Negi P;Dua K;Zacconi FC
通讯作者：
Zacconi FC