Bioengineered miR-124-3p prodrug selectively alters the proteome of human carcinoma cells to control multiple cellular components and lung metastasis in vivo
| Autor: | Neelu Batra, Hannah Petrek, Mei-Juan Tu, Linglong Deng, Aiming Yu, Ai-Xi Yu |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Proteomics
Junctions RNA therapy RM1-950 CDH2 Metastasis Imaging Focal adhesion IQGAP1 Bioengineer 2.1 Biological and endogenous factors General Pharmacology Toxicology and Pharmaceutics Cell adhesion Lung Cancer Cadherin Chemistry MiR-124-3p Plectin Cancer cell Cancer research Original Article Therapeutics. Pharmacology Biotechnology Junctional Adhesion Molecule A |
| Zdroj: | Acta Pharmaceutica Sinica. B Acta Pharmaceutica Sinica B, Vol 11, Iss 12, Pp 3950-3965 (2021) |
| ISSN: | 2211-3843 2211-3835 |
| Popis: | 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. Graphical abstract 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.Image 1 |
| Databáze: | OpenAIRE |
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