MicroRNA Regulation of Endothelial Junction Proteins and Clinical Consequence

Abstract

Cellular junctions play a critical role in structural connection and signal communication between cells in various tissues. Although there are structural and functional varieties, cellular junctions include tight junctions, adherens junctions, focal adhesion junctions, and tissue specific junctions such as PECAM-1 junctions in endothelial cells (EC), desmosomes in epithelial cells, and hemidesmosomes in EC. Cellular junction dysfunction and deterioration are indicative of clinical diseases. MicroRNAs (miRNA) are ~20 nucleotide, noncoding RNAs that play an important role in posttranscriptional regulation for almost all genes. Unsurprisingly, miRNAs regulate junction protein gene expression and control junction structure integrity. In contrast, abnormal miRNA regulation of junction protein gene expression results in abnormal junction structure, causing related diseases. The major components of tight junctions include zonula occluden-1 (ZO-1), claudin-1, claudin-5, and occludin. The miRNA regulation of ZO-1 has been intensively investigated. ZO-1 and other tight junction proteins such as claudin-5 and occludin were positively regulated by miR-126, miR-107, and miR21 in different models. In contrast, ZO-1, claudin-5, and occludin were negatively regulated by miR-181a, miR-98, and miR150. Abnormal tight junction miRNA regulation accompanies cerebral middle artery ischemia, brain trauma, glioma metastasis, and so forth. The major components of adherens junctions include VE-cadherin, β-catenin, plakoglobin, P120, and vinculin. VE-cadherin and β-catenin were regulated by miR-9, miR-99b, miR-181a, and so forth. These regulations directly affect VE-cadherin-β-catenin complex stability and further affect embryo and tumor angiogenesis, vascular development, and so forth. miR-155 and miR-126 have been shown to regulate PECAM-1 and affect neutrophil rolling and EC junction integrity. In focal adhesion junctions, the major components are integrin β4, paxillin, and focal adhesion kinase (FAK). Integrin β4 has been regulated by miR-184, miR-205, and miR-9. Paxillin has been regulated by miR-137, miR-145, and miR-218 in different models. FAK has been regulated by miR-7, miR-138, and miR-135. Deregulation of miRNAs is caused by viral infections, tumorigenesis, and so forth. By regulation of posttranscription, miRNAs manipulate junction protein expression in all cellular processes and further determine cellular fate and development. Elucidation of these regulatory mechanisms will become a new alternative therapy for many diseases, such as cancers and inflammatory diseases.

Oxygen tension modulates extracellular vesicles and its miRNA contents in bovine embryo culture medium

“…We found increased levels of miR‐98 in EVs isolated from the culture medium of embryo IVP in high compared to low oxygen tension. The miRNA‐98 regulates negatively tight junction mRNAs reducing protein levels (Zhuang, Peng, Mastej, & Chen, ). These results suggest that high oxygen tension has a detrimental effect on delivered microRNAs mediated by EVs and might be involved in delayed embryo development during the implantation phase.…”

Screening and verification of microRNA promoter methylation sites in hepatocellular carcinoma

“…The miRNAs corresponding to 7 CG sites associated with HCC vascular infiltration (hsa‐miR‐200c, hsa‐miR‐345, hsa‐miR‐9‐1, hsa‐miR‐15b, hsa‐miR‐107, hsa‐miR‐199a‐3p, and hsa‐miR‐184) were screened with the LASSO‐Logistic method and are closely related to angiogenesis 38–42 . Ghosh et al 39 found that miR‐199a‐3p was directly involved in HCC angiogenesis, invasion, and metastasis, and it inhibits the angiogenesis of HCC by inhibiting the expression of VEGF and its receptor.…”

Tumor‐derived exosomes enhance invasion and metastasis of salivary adenoid cystic carcinoma cells

“…Claudin‐5, as a member of Claudins family, is specifically expressed in endothelial cells different from epithelial cells . These two cell junction‐related proteins constitute the tight junction of endothelial cell‐cell tight junction (TJ) and maintain the stabilization of endothelial permeability and vascular endothelial barrier . SACC‐83 cell‐derived exosomes downregulated ZO‐1 and Claudin‐5 in endothelial cells destroyed the integrity of endothelial barrier.…”