Bioengineered miR-124-3p prodrug selectively alters the proteome of human carcinoma cells to control multiple cellular components and lung metastasis in vivo

• 作者: Linglong Deng Hannah Petrek Mei-Juan Tu Neelu Batra Ai-Xi Yu Ai-Ming Yu
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（12）
• 所属期刊栏目: Original articles
• 页码范围: 3950-3965
• 页数: 16页
• 语种: 英文

摘要

With the understanding of microRNA(miRNA or miR)functions in tumor initiation,pro-gression,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 pro-teins 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 junc-tions.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 exper-imental metastasis mouse model in vivo.These results connect miR-124-3p-PLEC signaling to other el-ements 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.