Original articles
Linglong Deng, Hannah Petrek, Mei-Juan Tu, Neelu Batra, Ai-Xi Yu, Ai-Ming Yu. Bioengineered miR-124-3p prodrug selectively alters the proteome of human carcinoma cells to control multiple cellular components and lung metastasis in vivo[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3950-3965

Bioengineered miR-124-3p prodrug selectively alters the proteome of human carcinoma cells to control multiple cellular components and lung metastasis in vivo
Linglong Denga,b, Hannah Petrekb, Mei-Juan Tub, Neelu Batrab, Ai-Xi Yua, Ai-Ming Yub
a. Department of Orthopaedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan 430072, China;
b. Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
Abstract:
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.
Key words:    RNA therapy    MiR-124-3p    Metastasis    Proteomics    Junctions    Cell adhesion    Bioengineer    Imaging   
Received: 2021-03-19     Revised: 2021-07-05
DOI: 10.1016/j.apsb.2021.07.027
Funds: This study is supported by the National Cancer Institute (No. R01CA225958 to Ai-Ming Yu, USA), National Institutes of Health. Ai-Xi Yu is supported by Hubei Province Scientific and Technological Innovation Key Project (No. 2019ACA136, China) and Hubei Province Medical Leader Talent Project (No. LJ20200405, China). Linglong Deng was supported by a fellowship from the Chinese Scholarship Council (No. 201906270202, China). The authors also appreciate the access to the Mouse Biology and Molecular Pharmacology Shared Resources funded by the UC Davis Comprehensive Cancer Center Support Grant awarded by the National Cancer Institute (No. P30CA093373, USA), National Institutes of Health.
Corresponding author: Ai-Xi Yu,E-mail:yuaixi@whu.edu.cn;Ai-Ming Yu,E-mail:aimyu@ucdavis.edu     Email:yuaixi@whu.edu.cn;aimyu@ucdavis.edu
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Linglong Deng
Hannah Petrek
Mei-Juan Tu
Neelu Batra
Ai-Xi Yu
Ai-Ming Yu

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