Long Non-Coding RNA MEG3 Downregulation Triggers Human Pulmonary Artery Smooth Muscle Cell Proliferation and Migration via the p53 Signaling Pathway

Abstract

Background/Aims: Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes, and many of which are likely to have functional roles in vascular remodeling. However, their functions in pulmonary arterial hypertension (PAH) remain largely unknown. Pulmonary vascular remodeling is an important pathological feature of PAH, leading to increased vascular resistance and reduced compliance. Pulmonary artery smooth muscle cells (PASMCs) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of PASMCs function. Herein, we determined whether long noncoding RNA–maternally expressed gene 3 (MEG3) was involved in PAH-related vascular remodeling. Methods: The arterial wall thickness was examined by hematoxylin and eosin (H&E) staining in distal pulmonary arteries (PAs) isolated from lungs of healthy volunteers and PAH patients. The expression level of MEG3 was analyzed by qPCR. The effects of MEG3 on human PASMCs were assessed by cell counting Kit-8 assay, BrdU incorporation assay, flow cytometry, scratch-wound assay, immunofluorescence, and western blotting in human PASMCs. Results: We revealed that the expression of MEG3 was significantly downregulated in lung and PAs of patients with PAH. MEG3 knockdown affected PASMCs proliferation and migration in vitro. Moreover, inhibition of MEG3 regulated the cell cycle progression and made more smooth muscle cells from the G₀/G₁ phase to the G₂/M+S phase and the process could stimulate the expression of PCNA, Cyclin A and Cyclin E. In addition, we found that the p53 pathway was involved in MEG3–induced smooth muscle cell proliferation. Conclusions: This study identified MEG3 as a critical regulator in PAH and demonstrated the potential of gene therapy and drug development for treating PAH.

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“…Current evidence has highlighted that lncRNA MEG3 was capable of targeting directly and activating p53 in various cell types . Consistent with these above reports, we identify that lncRNA MEG3 could directly bind to and regulate p53 expression in NMVMs by RIP and Western blot assays, but which were not entirely the same as Wu.et al research .…”

Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

“…The pathogenesis of PAH is characterized by pulmonary vascular remodeling with stiffening of the elastic proximal pulmonary arteries and thickening of the intimal and/or medial layer of muscular arteries, resulting from aberrant PASMC proliferation, migration and apoptosis [4,43,44]. In this study, excessive proliferation and migration and apoptosis resistance were observed in the in vitro cultured PASMCs derived from MCT-treated rats.…”

Mining Prognostic Significance of MEG3 in Human Breast Cancer Using Bioinformatics Analysis

“…Maternally expressed gene 3 (MEG3) is the first lncRNA that has been shown to function as a tumor suppressor and inhibit cell proliferation in numerous human cancer cell lines, and it is expressed in many normal human tissues [15][16][17]. Loss of MEG3 expression has been identified in many human tumors, including cervical cancer [18], retinoblastoma [19], ovarian carcinoma [20], gastric cancer [21], germ cell tumor [22], and squamous cell carcinoma [23], and such loss is indicative of poor prognosis.…”