MALAT1 Modulates TGF-β1-Induced Endothelial-to-Mesenchymal Transition through Downregulation of miR-145

Abstract

Background/Aims: Endothelial-to-mesenchymal transition (EndMT) plays significant roles under various pathological conditions including cardiovascular diseases, fibrosis, and cancer. EndMT of endothelial progenitor cells (EPCs) contributes to neointimal hyperplasia following cell therapy Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA) that promotes metastasis and cancer. MicroRNA-145 (miR-145) is a tumor suppressor that has been reported to inhibit SMAD3-mediated epithelial-to-mesenchymal transition (EMT) of cancer cells. In the present study, we investigated the role of MALAT1 and miR-145 in EndMT of human circulating EPCs induced by transforming growth factor beta1 (TGF-β1). Methods: Human circulating EPCs were isolated and characterized by fluorescence-activated cell sorting (FACS). Expression levels of EndMT markers were assessed by qRT-PCR and western blotting. Alpha-smooth muscle actin (α-SMA) expression was measured by cell immunofluorescence staining. The regulatory relationship between MALAT1 and miR-145 and its target genes, TGFBR2 (TGFβ receptortype II) and SMAD3 (mothers against decapentaplegic homolog 3) was analyzed using the luciferase reporter assay. Results: We found that EndMT of EPCs induced by TGF-β1 is accompanied by increased MALAT1 expression and decreased miR-145 expression, and MALAT1 and miR-145 directly bind and reciprocally repress each other in these cells. Dual-Luciferase Reporter assay indicated that miR-145 inhibits TGF-β1-induced EndMT by directly targeting TGFBR2 and SMAD3. Conclusions: MALAT1 modulates TGF-β1-induced EndMT of EPCs through regulation of TGFBR2 and SMAD3 via miR-145. Thus, the MALAT1-miR-145-TGFBR2/SMAD3 signaling pathway plays a key role in TGF-β1-induced EndMT.

Low-Intensity Pulsed Ultrasound Prevents the Oxidative Stress Induced Endothelial-Mesenchymal Transition in Human Aortic Endothelial Cells

“…EndMT can be induced by multiple factors via several interactive signaling pathways. The key factor in EndMT is the TGF-β super family that plays an indispensable role [14, 41]. This study demonstrated that H 2 O 2 -mediated oxidative stress induced EndMT in HAECs as indicated by the marked increases in the expression of mesenchymal cell marker genes and concordant decreases in endothelial cell marker genes, and these EndMT-related changes were abolished by LIPUS, indicating the anti-EndMT property of this ultrasound treatment.…”

“…In addition, accumulation of reactive oxygen species (ROS) can directly damage endothelial cells and indirectly modulate endothelial cell function via altering expression and function of the related genes [13]. EndMT is a cellular process where endothelial cells undergo significant morphological changes with loss of their endothelial characteristics and gain of mesenchymal properties that ultimately leads to transformation into stromal fibroblasts [14]. …”

TGFβ1-Smad Signaling Pathway Participates in Interleukin-33 Induced Epithelial-to-Mesenchymal Transition of A549 Cells

“…One previous study [31] also reported that the TGFβ1-smad signaling pathway is an important up-stream mechanism of EMT. Meanwhile, the TGFβ1-smad is positively correlated with the IL-33 expression.…”

Histone Deacetylases Promote ER Stress Induced Epithelial Mesenchymal Transition in Human Lung Epithelial Cells

“…However, a recent study showed that TGF-β mediated EMT in retinal pigment epithelium through complex interplay between Smad pathway, Akt, p38MAPK, ERK1/2 pathways and Jagged/Notch pathway [26]. In addition, miR-145 was recently reported to modulate TGF-β1/Smad3 signaling to regulate endothelial-to-mesenchymal transition [27]. Further studies are necessary to investigate the crosstalk of Smad pathway with other pathways in mediating EMT of alveolar epithelial cells exposed to ER stress.…”