Smooth Muscle Enriched Long Noncoding RNA (
            <i>SMILR</i>
            ) Regulates Cell Proliferation

Accumulating evidence has indicated that lncRNA NEAT1 exerts critical roles in cancers. So far, the detailed biological role and mechanisms of NEAT1 which are responsible for human gastric cancer (GC) is still largely unknown. Here, we observed that NEAT1 and STAT3 expression were significantly upregulated in human gastric cancer cells including BGC823, SGC-7901, AGS, MGC803 and MKN28 cells compared to normal gastric epithelial cells GES-1 while miR-506 was downregulated. We inhibited NEAT1 and observed that NEAT1 inhibition was able to repress the growth, migration and invasion of gastric cancer cells. Reversely, overexpression of NEAT1 exhibited an increase ability of gastric cancer progression in BGC823 and SGC-7901 cells. Bioinformatics analysis, dual luciferase reporter assays, RIP assays and RNA pull-down tests validated the negative binding correlation between NEAT1 and miR-506. In addition, it was found that miR-506 can modulate expression of NEAT1 in vitro. STAT3 was predicted as an mRNA target of miR-506 and miR-506 mimics can suppress STAT3 mRNA expression. Subsequently, it was observed that downregulation of NEAT1 can restrain gastric cancer development by decreasing STAT3 which can be reversed by miR-506 inhibitors. Therefore, it was hypothesized in our study that NEAT1 can be recognized as a ceRNA to modulate STAT3 by sponging miR-506 in gastric cancer. In conclusion, we implied that NEAT1 can serve as an important biomarker in gastric cancer diagnosis and treatment. This article is protected by copyright. All rights reserved.

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“…21 They are manifested to be involved in biological processes. It was predicted that STAT3 can be provided as an miR-506 target.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA NEAT1‐modulated miR‐506 regulates gastric cancer development through targeting STAT3

Tan

Wang

Liu

et al. 2019

J of Cellular Biochemistry

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“…These observations clearly demonstrate that LMCD1 mediates VSMC DNA synthesis in a species-specific manner. As LMCD1 was only involved in HASMC DNA synthesis and due to lack of access to human restenosis artery tissue samples, we used human normal and atherosclerotic coronary artery samples as an in vivo model, since VSMC proliferation is a common phenomenon in both restenosis and during early development of atherosclerosis (24)(25)(26)(27)(28). It was interesting to note that LMCD1 expression was induced highly in SMC and co-localized with the cell proliferation marker Ki67 in human atherosclerotic lesions as compared to normal artery ( Figure 7E).…”

Section: To Identify Thrombin-induced Genes In Hasmcsmentioning

confidence: 99%

LIM and cysteine-rich domains 1 is required for thrombin-induced smooth muscle cell proliferation and promotes atherogenesis

Janjanam

Zhang

Mani

et al. 2018

Journal of Biological Chemistry

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Restenosis arises after vascular injury and is characterized by arterial wall thickening and decreased arterial lumen space. Vascular injury induces the production of thrombin, which in addition to its role in blood clotting, acts as a mitogenic and chemotactic factor. In exploring the molecular mechanisms underlying restenosis, here we identified LIM and cysteinerich domains 1 (LMCD1) as a gene highly responsive to thrombin in human aortic smooth muscle cells (HASMCs). Of note, LMCD1 depletion inhibited proliferation of human but not murine vascular smooth muscle cells. We also found that by physically interacting with E2F transcription factor 1 (E2F1), LMCD1 mediates thrombin-induced expression of the cell division cycle 6 (CDC6) gene in the stimulation of HASMC proliferation. Thrombin-induced LMCD1 and CDC6 expression exhibited a requirement for protease-activated receptor 1 (PAR1)-mediated Gαq/11-dependent activation of phospholipase C β3 (PLCβ3). Moreover, the expression of LMCD1 was highly induced in smooth muscle cells located at human atherosclerotic lesions and correlated with CDC6 expression and that of the proliferation marker Ki67. Furthermore, the LMCD1-and SMCαactin-positive cells had higher cholesterol levels in the atherosclerotic lesions. In conclusion, these findings indicate that by acting as a coactivator with E2F1 in CDC6 expression, LMCD1 stimulates HASMC proliferation and thereby promotes human atherogenesis, suggesting an involvement of LMCD1 in restenosis.Restenosis, characterized by arterial wall thickening and decreased arterial lumen space, occurs as a response to vascular injury (1, 2). Vascular smooth muscle cell (VSMC) migration and proliferation in the tunica intima is the root cause of restenosis (1-3). Vascular injury stimulates coagulation cascade activation and produces substantial amounts of thrombin (4). The thrombus formed due to injury can serve as a reservoir of active thrombin (5). Thrombin, in addition to its vital role in blood clotting, acts as a mitogen and chemotactic factor to a variety of cell types, including peripheral blood monocytes and VSMCs (6-8). In identifying the thrombin-induced genes by microarray analysis, we found that a novel LIM and cysteine-rich domains 1 (LMCD1) gene was induced by thrombin in a sustained manner in human aortic smooth muscle cells (HASMCs). LMCD1, a member of the LIM protein family, contains a novel cysteine-rich domain at the N-terminus, a central PET (Prickle, Espinas and Testin) domain and two LIM domains at the C-terminal region (9). The proteins containing LIM domains are known to have distinct functions in gene expression, cell adhesion, cytoskeleton remodeling, and signal transduction (10). Although the cellular functions of many LIM proteins have been studied (10), there are only a limited number of reports on the biological functions of LMCD1. It was reported that LMCD1 plays a role in the development of cardiac hypertrophy (11). Another study suggests that LMCD1 acts as a transcriptional repressor for GATA6, a zi...

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“…However, no change in the expression of HAS1 and HAS3 isoforms was observed, or for HAS2-AS1 lncRNA or the ZHX2 gene, indicating that the SMILR knockdown effect is specific to HAS2. Increased expression of SMILR was observed in human samples from patients with unstable atherosclerotic plaques and in plasma from patients with high plasma C-reactive protein levels, suggesting SMILR may be a driver of VSMC proliferation, with potential implications in atherogenesis [33]. …”

Section: Lncrnas In Smooth Muscle Cellsmentioning

confidence: 99%

Long noncoding RNAs in cardiovascular disease, diagnosis, and therapy

Haemmig

Simion

Yang

et al. 2017

Current Opinion in Cardiology

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Purpose of review Long non-coding RNAs (lncRNAs) have emerged as powerful regulators of nearly all biological processes. Their cell-type and tissue-specific expression in health and disease provides new avenues for diagnosis and therapy. This review highlights the role of lncRNAs that are involved in cardiovascular disease (CVD) with a special focus on cell types involved in cardiac injury and remodelling, vascular injury, angiogenesis, inflammation, and lipid metabolism. Recent findings Almost 98% of the genome does not encode for proteins. LncRNAs are among the most abundant type of RNA in the non-coding genome. Accumulating studies have uncovered novel lncRNA-mediated regulation of CVD-associated genes, signalling pathways, and pathophysiological responses. Targeting lncRNAs in vivo using short antisense oligonucleotides or by gene editing has provided important insights into disease pathogenesis through epigenetic, transcriptional, or translational mechanisms. Although cross-species conservation still remains a major obstacle, there is increasing appreciation that altered expression of lncRNAs associates with stage-specific CVD pathologies and in human patient cohorts, providing new opportunities for diagnosis and therapy. Summary A better understanding of lncRNAs will not only fundamentally improve our understanding of key signaling pathways in CVD, but also aid in the development of effective new therapies and RNA-based biomarkers.

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Smooth Muscle Enriched Long Noncoding RNA ( SMILR ) Regulates Cell Proliferation

Abstract: Supplemental Digital Content is available in the text.

Cited by 186 publications

References 59 publications

Long noncoding RNA NEAT1‐modulated miR‐506 regulates gastric cancer development through targeting STAT3

Long noncoding RNA NEAT1‐modulated miR‐506 regulates gastric cancer development through targeting STAT3

LIM and cysteine-rich domains 1 is required for thrombin-induced smooth muscle cell proliferation and promotes atherogenesis

Long noncoding RNAs in cardiovascular disease, diagnosis, and therapy

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