CLDN5 affects lncRNAs acting as ceRNA dynamics contributing to regulating blood‑brain barrier permeability in tumor brain metastasis

Abstract

The blood‑brain barrier (BBB) constitutes an efficient organization of tight junctions that limits the delivery of tumor to the brain. The principal tight junction protein in BBB is claudin‑5 (CLDN5), but its mechanism of action remains largely unknown. Long non‑coding RNAs (lncRNAs) are aberrantly expressed in many cancers, some lncRNAs play key roles in regulating BBB permeability and are involved in tumor brain metastasis. In particular, lncRNAs can function as competing endogenous RNAs (ceRNAs). Herein, we investigated whether ceRNA dysregulation is associated with alterations of the level of CLDN5 in human brain vascular endothelial hCMEC/D3 cells. The Affymetrix Human Transcriptome Array 2.0 and Affymetrix GeneChip miRNA 4.0 Array were used to detect the expression levels of 2,578 miRNAs, 22,829 lncRNAs, and 44,699 mRNAs in pLL3.7‑CLDN5‑transfected and pLL3.7 control hCMEC/D3 cells. The distinctly expressed miRNAs, lncRNAs, and mRNAs were subjected to construction of miRNA‑lncRNA‑mRNA interaction network. A total of 41 miRNAs, 954 lncRNAs, and 222 mRNAs were found to be differentially expressed between the CLDN5‑overexpressing and control group. 148 lncRNA acting as ceRNAs were identified based on the miRNA‑lncRNA‑mRNA interaction network. The function of differential mRNA in the network was determined by GO and pathway analysis. The potential roles of the 27 ceRNAs were revealed, the possible biology functions of these regulatory ceRNAs mainly included tight junction, focal adhesion, cell‑cell adhesion, cell growth and apoptosis. The identified sets of miRNAs, lncRNAs and mRNAs specific to CLDN5‑overexpressing hCMEC/D3 cells were verified by quantitative real‑time RT‑PCR experiment. Our study predicts the biological functions of a multitude of ceRNAs associated with the alteration of CLDN5 in brain vascular endothelial cells. Our data suggest that these dysregulated ceRNAs, in conjunction with the high CLDN5 levels, could serve as useful targets of prevention of brain metastasis formation. Further studies are warranted to determine the role of these ceRNAs in facilitating the function of CLDN5 in brain‑tumor barrier.

Genes co-related with poor prognosis of patients with lung cancer via bioinformatical approaches

“…Ma discovered CLDN5 was closely related to brain metastases from lung cancer [33]. In 2019, Jia indicated that high-dose bevacizumab likely increased lung tumor invasion and potential metastatic abilities through down-regulating CLDN5 [34].Moreover, CLDN5 showed a close relationship with mental illness, such as depression [35], schizophrenia [36], brain edema following fatal heat stroke [37] and tumor brain metastasis [38]. showed that PECAM1 was found to be related to angiogenesis of the lung cancer [39][40].…”

The Role of Long Non-Coding RNAs in Intracranial Aneurysms and Subarachnoid Hemorrhage

“…There are several obstacles facing the development of lncRNA-based therapeutics for IAs. One of the obstacles impeding development of lncRNA-based therapeutics is low delivery efficacy to the brain vasculature and the likely need for repeated delivery [68]. Second, the functions and mechanisms used by lncRNAs are much more complex and diversified than other non-coding RNAs [3].…”

“…Fourthly, challenges for lncRNAs delivery remain with respect to their efficiency and tissue specificity [70]. While viral vectors induce immunogenicity, challenges for delivery lncRNAs may be overcome using chemical functionalization of nanoparticles surface targeted to specific ligands overexpressed by cells in the cerebral vessel wall in response to relevant stimuli [68,71]. In addition, most lncRNAs lack conservation between species, which restricts the utility of preclinical animal models.…”

The year in review: progress in brain barriers and brain fluid research in 2018

“…microRNA-143, -146a, -149-5p, -21, -96 and -155 [31–36]). Interestingly, in addition, Ma et al [37] found that claudin-5 affects the expression of long non-coding RNAs (lncRNAs) in brain endothelial cells thereby regulating BBB properties in brain metastases.…”