ABSTRACT
BACKGROUND AND AIMS: Low-grade chronic inflammation was reported to serve as a distinctive pathophysiologic feature of coronary artery disease (CAD), the leading cause of death around the world. Herein, the current study aimed to explore whether and how microRNA-34c-5p (miR-34c-5p), a miRNA enriched in extracellular vesicles (EVs) originated from the activated platelet (PLT-EVs), affects the inflammation of human coronary artery endothelial cells (HCAECs). METHODS AND RESULTS: HCAECs were established as an in vitro cell model using oxidized low-density lipoprotein (ox-LDL). miR-34c-5p, an abundant miRNA in PLT-EVs, can be transferred to HCAECs and target PODXL by binding to its 3'UTR. Gain- and loss-of-function experiments of miR-34c-5p and podocalyxin (PODXL) were performed in ox-LDL-induced HCAECs. Subsequently, HCAECs were subjected to co-culture with PLT-EVs, followed by detection of the expression patterns of key pro-inflammatory factors. Either miR-34c-5p mimic or PLT-EVs harboring miR-34c-5p attenuated the ox-LDL-evoked inflammation in HCAECs by suppressing interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α). By blocking the P38 MAPK signaling pathway, miR-34c-5p-mediated depletion of PODXL contributed to protection against ox-LDL-induced inflammation. In vitro findings were further validated by findings observed in ApoE knock-out mice. Additionally, miR-34c-5p in PLT-EVs showed an athero-protective role in the murine model. CONCLUSION: Altogether, our findings highlighted that miR-34c-5p in PLT-EVs could alleviate inflammation response in HCAECs by targeting PODXL and inactivation of the P38 MAPK signaling pathway.
Subject(s)
Extracellular Vesicles , MicroRNAs , 3' Untranslated Regions , Animals , Apolipoproteins E/genetics , Coronary Vessels/metabolism , Endothelial Cells/metabolism , Extracellular Vesicles/metabolism , Humans , Inflammation/genetics , Inflammation/metabolism , Inflammation/prevention & control , Interleukin-1beta , Interleukin-6/metabolism , Lipoproteins, LDL/metabolism , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Sialoglycoproteins , Signal Transduction , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Long noncoding RNAs (lncRNAs) are implicated tumor development in a range of different cancers, including pancreatic cancer (PC). Cancer stem cells (CSCs), a drug-resistant cancer cell subset, drive tumor progression in PC. In this work, we aimed to investigate the mechanism by which lncRNA LINC00261 affects the biological functions of CSCs during the progression of PC. Microarray analysis of differentially expressed genes and lncRNAs suggested that LINC00261 is downregulated in PC. Both LINC00261 and ITIH5 were confirmed to be downregulated in PC cells and PC stem cells. Gain-of-function and loss-of-function investigations were performed to analyze their effects on cell proliferation, drug resistance, cell cycle distribution, self-renewal, invasion, and ultimately overall tumorigenicity. These experiments revealed that the expression of stem cell markers was reduced, and cell proliferation, self-renewal ability, cell invasion, drug resistance, and tumorigenicity were all suppressed by upregulation of LINC00261 or ITIH5. The results of dual-luciferase reporter gene, ChIP, and RIP assays indicated that LINC00261 binds directly to GATA6, increasing its activity at the ITIH5 promoter. The presence of LINC00261 and GATA6 inhibited the self-renewal and tumorigenesis of PC stem cells, while silence of ITIH5 rescued those functions. Collectively, this study identifies the tumor suppressive activity of LINC00261 in PC, showing that this lncRNA limits the functions of PC stem through an ITIH5/GATA6 regulatory pathway.
ABSTRACT
MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression by binding to the 3' untranslated region of their target mRNAs. Recent work supports a role for miRNAs in the initiation and progression of human cancer. miRNA-214 not only mediates differentiation, senescence, angiogenesis, cell migration and virus replication but also acts as a tumor suppressor gene and oncogene. Increasing evidence indicates that miRNA-214 may serve as a biomarker in some cancer types. The aim of this review is to highlight and clarify the complexity of miRNA-214 activity, emphasizing its significant therapeutic and diagnostic potential.