Long non-coding RNA MALAT1 silencing elevates microRNA-26a-5p to ameliorate myocardial injury in sepsis by reducing regulator of calcineurin 2.

OBJECTIVE: Sepsis is a leading cause of morbidity and mortality after surgery. We aimed to explore the role of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) sponging microRNA-26a-5p in sepsis-induced myocardial injury by regulating regulator of calcineurin 2 (Rcan2). METHODS: HL-1 cells were incubated with lipopolysaccharide (LPS) to induce in vitro cardiomyocyte injury models, which were then treated with silenced MALAT1 vector, miR-26a-5p mimic or Rcan2 overexpression vector. Next, inflammatory factor level and apoptosis of cells were determined. The in vivo mouse models were constructed by intraperitoneal injection of LPS. The modeled mice were injected with relative oligonucleotides and the pathology, apoptosis, and inflammation in mouse myocardial tissues were assessed. Expression of MALAT1, miR-26a-5p and Rcan2 in vivo and in vitro was evaluated. RESULTS: MALAT1 and Rcan2 were upregulated while miR-26a-5p was downregulated in LPS-treated HL-1 cells and mice. MALAT1 silencing or miR-26a-5p upregulation suppressed LPS-induced inflammation and apoptosis of cardiomyocytes in cellular and animal models. These effects of elevated miR-26a-5p could be reversed by upregulating Rcan2, and MALAT1 knockdown-induced ameliorative impacts could be reversed by miR-26a-5p downregulation. CONCLUSION: MALAT1 silencing elevated miR-26a-5p to ameliorate LPS-induced myocardial injury by reducing Rcan2. Our research may provide novel biomarkers for the treatment of sepsis.

LncRNA MALAT1 Participates in Protection of High-Molecular-Weight Hyaluronan against Smoke-Induced Acute Lung Injury by Upregulation of SOCS-1.

Smoke-induced acute lung injury (ALI) is a grievous disease with high mortality. Despite advances in medical intervention, no drug has yet been approved by the Food and Drug Administration (FDA) for ALI. In this study, we reported that pretreatment with high-molecular-weight hyaluronan (1600 kDa, HA1600) alleviated pulmonary inflammation and injury in mice exposed to smoke and also upregulated long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), as well as suppressor of cytokine signaling-1 (SOCS-1), in the lung tissues. Next, we overexpressed MALAT1 in the lungs by intratracheal administration of adenovirus cloned with MALAT1 cDNA and found that the survival of mice after smoke exposure was improved. Moreover, pulmonary overexpression of MALAT1 ameliorated smoke-induced ALI in mice and elevated the level of SOCS-1 in the lungs. In conclusion, the results pointed out that HA1600 exerted a protective effect against smoke-induced ALI through increasing the MALAT1 level and the subsequent SOCS-1 expression. Our study provides a potential therapeutic approach to smoke-induced ALI and a novel insight into the mechanism of action of HA1600.

MALAT1 shuttled by extracellular vesicles promotes M1 polarization of macrophages to induce acute pancreatitis via miR-181a-5p/HMGB1 axis.

Acute pancreatitis (AP) is a serious condition carrying a mortality of 25-40%. Extracellular vesicles (EVs) have reported to exert potential functions in cell-to-cell communication in diseases such as pancreatitis. Thus, we aimed at investigating the mechanisms by which EV-encapsulated metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) might mediate the M1 polarization of macrophages in AP. Expression patterns of MALAT1, microRNA-181a-5p (miR-181a-5p) and high-mobility group box 1 protein (HMGB1) in serum of AP patients were determined. EVs were isolated from serum and pancreatic cells. The binding affinity among miR-181a-5p, MALAT1 and HMGB1 was identified. AP cells were co-cultured with EVs from caerulein-treated MPC-83 cells to determine the levels of M1/2 polarization markers and TLR4, NF-κB and IKBa. Finally, AP mouse models were established to study the effects of EV-encapsulated MALAT1 on the M1 polarization of macrophages in AP in vivo. MALAT1 was transferred into MPC-83 cells via EVs, which promoted M1 polarization of macrophages in AP. MALAT1 competitively bound to miR-181a-5p, which targeted HMGB1. Moreover, MALAT1 activated the TLR4 signalling pathway by regulating HMGB1. EV-encapsulated MALAT1 competitively bound to miR-181a-5p to upregulate the levels of IL-6 and TNF-α by regulating HMGB1 via activation of the TLR4 signalling pathway, thereby inducing M1 polarization of macrophages in AP. In vivo experimental results also confirmed that MALAT1 shuttled by EVs promoted M1 polarization of macrophages in AP via the miR-181a-5p/HMGB1/TLR4 axis. Overall, EV-loaded MALAT1 facilitated M1 polarization of macrophages in AP via miR-181a-5p/HMGB1/TLR4, highlighting a potential target for treating AP.

CCL21 activation of the MALAT1/SRSF1/mTOR axis underpins the development of gastric carcinoma.

BACKGROUND: As a significant cause of malignancy mortality, gastric carcinoma (GC) has been well documented to be an often-fatal diagnosis. Despite the limitations of effective therapy, immunotherapy has emerged as a promising therapeutic approach capable of killing cancer cells via the immune system. The current study was conducted to investigate the effect of cytokine C-C motif chemokine ligand 21 (CCL21) on GC progression through the metastasis-associated lung adenocarcinoma transcript 1/serine arginine-rich splicing factor 1/mammalian target of rapamycin (MALAT1/SRSF1/mTOR) axis. METHODS: Bioinformatics analysis was conducted to identify the key genes associated with GC and to subsequently predict their downstream genes. The effect of CCL21, MALAT1, and SRSF1 on the malignant phenotypes and epithelial-mesenchymal transition (EMT) of SGC-7901 and MGC-803 cells in-vitro and the tumorigenesis of SGC-7901 and MGC-803 cells in-vivo were assessed by expression determination and plasmid transfection. Additionally, RNA pull-down and RNA binding protein immunoprecipitation experiments were performed to determine the MALAT1-microRNA-202-3p (miR-203-3p) interaction and miR-202-3p-SRSF1 interaction followed by the analysis of their effect on the mTOR pathway. RESULTS: CCL21 was identified as a key GC immune gene. Overexpressed CCL21, MALAT1, and SRSF1 along with poorly expressed miR-202-3p were identified in the GC cells. CCL21 induced the MALAT1 expression in a time- and dose-dependent manner. Functionally, MALAT1 targeted miR-202-3p but upregulated SRSF1 and activated mTOR. Crucially, evidence was obtained indicating that CCL21 promoted both the malignant phenotypes and EMT of SGC-7901 and MGC-803 cells in-vitro and the tumorigenesis of SGC-7901 and MGC-803 cells in-vivo by increasing the MALAT1-induced upregulation of SRSF1. CONCLUSIONS: Taken together, the key observations of our study provide evidence that CCL21 enhances the progression of GC via the MALAT1/SRSF1/mTOR axis, providing a novel therapeutic target for the treatment of GC.

Targeting MALAT1 and miRNA-181a-5p for the intervention of acute lung injury/acute respiratory distress syndrome.

BACKGROUND: ALI/ARDS is a severe lung injury leading to refractory respiratory failure, accounting for high morbidity and mortality. However, therapeutic approaches are rather limited. Targeting long non-coding RNA MALAT1 and microRNA miR-181a-5p might be potential option for ALI/ARDS intervention. OBJECTIVE: We aimed to investigate the role of MALAT and miR-181a-5p in the pathogenesis of ALI/ARDS, and test the therapeutic effects of targeting MALAT and miR-181a-5p for ALI/ARDS intervention in vitro. METHODS: MALAT1 and miR-181a-5p levels were measured in plasma from ALI/ARDS patients. In vitro human pulmonary microvascular endothelial cell (HPMEC) injury was induced by LPS treatment, and molecular targets of MALAT1 and miR-181a-5p were explored by molecular biology approaches, mainly focusing on cell apoptosis and vascular inflammation. Interaction between MALAT1 and miR-181a-5p was also detected. Finally, the effects of targeting MALAT1 and miR-181a-5p for ALI/ARDS intervention were validated in a rat ALI/ARDS model. RESULTS: MALAT1 upregulation and miR-181a-5p downregulation were observed in ALI/ARDS patients. Transfection of mimic miR-181a-5p into HPMECs revealed decreased Fas and apoptosis, along with reduced inflammatory factors. Fas was proved to be a direct target of miR-181a-5p. Similar effects were also present upon MALAT1 knockdown. As for the interaction between MALAT1 and miR-181a-5p, MALAT1 knockdown increased miR-181a-5p expression. Knocking down of MALAT1 and miR-181a-5p could both improve the outcome in ALI/ARDS rats. CONCLUSION: MALAT1 antagonism or miR-181a-5p could both be potential therapeutic strategies for ALI/ARDS. Mechanistically, miR-181a-5p directly inhibits Fas and apoptosis, along with reduced inflammation. MALAT1 negatively regulates miR-181a-5p.

Long noncoding RNA MALAT1 contributes to pregnancy-induced hypertension development by enhancing oxidative stress and inflammation through the regulation of the miR-150-5p/ET-1 axis.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified previously in the pathogenesis of hypertension and some gestational diseases. However, the biological functions of MALAT1 in pregnancy-induced hypertension (PIH) are still poorly understood. Herein, we aim to explore the functional relevance of MALAT1 in PIH and to explain the potential underlying mechanisms. We found that the levels of ET-1 and MALAT1 were upregulated and that of miR-150-5p were downregulated in the serum of pregnant women with PIH and the aortic endothelial cells (ECs) of reduced uterine perfusion pressure (RUPP)-induced rat models. In aortic ECs, MALAT1 could competitively bind to miR-150-5p to upregulate the expression of ET-1. The MALAT1/miR-150-5p/ET-1 axis regulated the expression of endothelin B receptor (ETBR) in aortic ECs leading to oxidative stress imbalance and increased the release of proinflammatory cytokines (IL-18 and IL-1ß), which concurrently activated the NF-κB pathway to regulate the ETBR expression and to stimulate smooth muscle cell (SMC) contraction. Furthermore, silencing MALAT1 could alleviate the hypertensive symptoms of RUPP-induced rat models. Taken conjointly, the upregulation of MALAT1 can reduce the expression of ET-1 by competitively binding to miR-150-5p, which enhances the expression of ETBR via the activation of the NF-κB pathway in SMCs, thus exacerbating the hypertensive symptoms in the RUPP-induced rat models.

Peripheral Blood-Based DNA Methylation of Long Non-Coding RNA H19 and Metastasis-Associated Lung Adenocarcinoma Transcript 1 Promoters are Potential Non-Invasive Biomarkers for Gastric Cancer Detection.

INTRODUCTION: The early diagnosis and detection could greatly improve the clinical outcome of gastric cancer (GC) patients. However, the non-invasive biomarkers for GC detection remain to be identified. METHOD: We used online databases (GEPIA, UALCAN, Kaplan-Meier plotter, TIMER, and MEXPRESS) to explore the association between H19 or metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression in tissues and the occurrence, development, prognosis, the levels of immune cell infiltration, and methylation of GC; the correlation between mRNA expression and DNA methylation levels of genes were also examined. Methylation levels of H19 or MALAT1 in peripheral blood were compared between 150 GC patients and 100 healthy controls (HCs). Predictive nomograms were constructed among female and male groups for GC diagnosis. The calibration curves, Hosmer-Lemeshow test, and decision curve analysis were also used to examine the nomograms' predictive ability and clinical values. RESULTS: Using multiple online databases, we found that the mRNA expressions of H19 and MALAT1 in tissues were related to the occurrence of GC, and such expressions were associated with immune cell infiltration of GC and negatively correlated with DNA methylation levels of H19 and MALAT1. H19 gene, H19C island, and MALAT1B island, as well as 20 CpG sites were hypermethylated in peripheral blood of GC patients compared with HCs; similar results were also found in female and male groups (P < .05 for all). The combination of H19c3, H19c4, MALAT1b12, and age, as well as the combination of H19b7, H19c1, H19c5, and age in the nomograms could distinguish GC patients from HCs in the female group and male group, respectively. CONCLUSION: We found statistically significant hypermethylation of H19 and MALAT1 promoters in GC patients, and meaningful sensitivity and specificity of MALAT1 and H19 methylation in discriminating GC and HCs were observed in both female and male groups, which indicates that the peripheral blood-based DNA methylation of H19 and MALAT1 could act as potential non-invasive biomarkers for the diagnosis of GC.

LncRNA MALAT1 Facilitates Ovarian Cancer Progression through Promoting Chemoresistance and Invasiveness in the Tumor Microenvironment.

Upregulation of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1, also known as nuclear-enriched abundant transcript 2 (NEAT2) or LINC00047) was found in various solid tumors, including epithelial ovarian cancer (EOC). MALAT1 is a long noncoding (lnc)RNA that regulates many functional signaling pathways, including tumorigenesis. Herein, we observed the consistent upregulation of MALAT1 in MYST4-overexpressing cell lines, while MALAT1 was frequently found to be upregulated in various types of clinical carcinoma tissues, especially EOC. To further investigate the lncRNA MALAT1 in EOC progression, the transduced overexpression of MALAT1 in EOC cell lines and cancer-associated fibroblasts (CAFs) was employed. We found that MALAT1 overexpression in EOC cell lines significantly increased drug resistance, cell migration, and invasion. Furthermore, the concomitant overexpression of MALAT1 in EOC cells and CAFs dramatically increased EOC cell invasion. Accordingly, a mechanistic investigation of MALAT1 overexpression in EOC cells showed that expressions of the cytokines interleukin (IL)-1ß and p-P38/p-NFκB/Cox2/prostaglandin E2 (PGE2) signaling were significantly increased, which stimulated inflammatory responses, whereas cell apoptosis was inhibited due to increased Bcl-2 levels and reduced Caspase3 levels. After MALAT1 was overexpressed in EOC cells, and the cyclin D1, p-PI3K, and p-Akt expressions increased, suggesting the promotion of tumor cell proliferation, while increased zinc finger E-box-binding homeobox-2 (ZEB2), yes-associated protein (YAP), and vimentin expression with E-cadherin downregulation indicated the enhancement of the epithelial-to-mesenchymal transition (EMT) in terms of metastasis, thereby triggering EOC progression. Together, our findings demonstrate how MALAT1 overexpression facilitates an oncogenic function through inhibiting tumor cell apoptosis, combined with increasing tumor cell inflammation, proliferation, and invasion in the EOC tumor microenvironment. MALAT1 is thus a potential diagnostic marker and therapeutic for this malignancy.

Suppression of long noncoding RNA MALAT1 inhibits the development of uveal melanoma via microRNA-608-mediated inhibition of HOXC4.

This study explored the effects of the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on the development of uveal melanoma. Moreover, the role of the MALAT1/microRNA-608 (miR-608)/homeobox C4 (HOXC4) axis was assessed by evaluating the proliferation, invasion, and migration, as well as the cell cycle distribution of uveal melanoma in vitro after knocking down MALAT1 or HOXC4 and/or overexpression of miR-608 in uveal melanoma cells (MUM-2B and C918). Moreover, the effects of the MALAT1/miR-608/HOXC4 axis in uveal melanoma in vivo were further evaluated by injecting the C918 cells into the NOD/SCID mice. HOXC4 was found to be a gene upregulated in uveal melanoma, while knockdown of its expression resulted in suppression of uveal melanoma cell migration, proliferation, and invasion, as well as cell cycle progression. In addition, the upregulation of miR-608 reduced the expression of HOXC4 in the uveal melanoma cells, which was rescued by overexpression of MALAT1. Hence, MALAT1 could upregulate the HOXC4 by binding to miR-608. The suppressed progression of uveal melanoma in vitro by miR-608 was rescued by overexpression of MALAT1. Additionally, in vivo assays demonstrated that downregulation of MALAT1 could suppress tumor growth through downregulation of HOXC4 expression via increasing miR-608 in uveal melanoma. In summary, MALAT1 downregulation functions to restrain the development of uveal melanoma via miR-608-mediated inhibition of HOXC4.

Long non-coding RNA MALAT1 targeting STING transcription promotes bronchopulmonary dysplasia through regulation of CREB.

Bronchopulmonary dysplasia (BPD) is a severe complication of preterm infants characterized by increased alveolarization and inflammation. Premature exposure to hyperoxia is believed to be a key contributor to the pathogenesis of BPD. No effective preventive or therapeutic agents have been created. Stimulator of interferon gene (STING) is associated with inflammation and apoptosis in various lung diseases. Long non-coding RNA MALAT1 has been reported to be involved in BPD. However, how MALAT1 regulates STING expression remains unknown. In this study, we assessed that STING and MALAT1 were up-regulated in the lung tissue from BPD neonates, hyperoxia-based rat models and lung epithelial cell lines. Then, using the flow cytometry and cell proliferation assay, we found that down-regulating of STING or MALAT1 inhibited the apoptosis and promoted the proliferation of hyperoxia-treated cells. Subsequently, qRT-PCR, Western blotting and dual-luciferase reporter assays showed that suppressing MALAT1 decreased the expression and promoter activity of STING. Moreover, transcription factor CREB showed its regulatory role in the transcription of STING via a chromatin immunoprecipitation. In conclusion, MALAT1 interacts with CREB to regulate STING transcription in BPD neonates. STING, CREB and MALAT1 may be promising therapeutic targets in the prevention and treatment of BPD.

Negative feedback of NF-κB signaling by long noncoding RNA MALAT1 controls lipopolysaccharide-induced inflammation injury in human lung fibroblasts WI-38.

The study was designed to elucidate the regulatory mechanism of long noncoding RNA human metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in lipopolysaccharides (LPS)-caused inflammation injury in human lung fibroblasts WI-38. WI-38 cells were stimulated with LPS to construct acute pneumonia cell model. MALAT1 in LPS-stimulated WI-38 cells was examined. LPS-induced inflammation injury was estimated using viability, apoptosis, and cytokine secretion including interleukin-1ß (IL-1ß) and IL-6. Furthermore, the modulatory relations of MALAT1 and nuclear factor-kappa B (NF-κB) signaling were explored. We found that the sensitivity of WI-38 cells to apoptosis was enhanced by LPS-caused inflammation. Moreover, LPS promoted MALAT1 expression which was found to alleviate LPS-caused damages. Besides, NF-κB p65 overexpression resulted in an increased expression of MALAT1, and MALAT1 was identified as a target gene of p65. Furthermore, overexpression of MALAT1 reduced NF-κB activation. Pulldown assay showed that MALAT1 could directly interact with p65. Taken together, our findings revealed that MALAT1 was upregulated in LPS-stimulated WI-38 cells. Through directly interacting with p65, MALAT1 blocked LPS-caused activation of NF-κB and repressed LPS-induced inflammation injury. MALAT1 may serve as a potential diagnostic indicator or therapeutic target for pneumonia.

MALAT1 affects hypoxia-induced vascular endothelial cell injury and autophagy by regulating miR-19b-3p/HIF-1α axis.

Cardiovascular disease has become the leading cause of death in the world. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in cardiovascular disease, such as stroke. However, the role of MALAT1 in hypoxia (HYP)-induced vascular endothelial cells (VECs) remains unclear. In the present study, HYP-treated human umbilical vein endothelial cells (HUVECs) were utilized to simulate HYP-induced VEC injury. It was found that after HYP treatment, the levels of MALAT1 and hypoxia-induced factor-1 (HIF-1α) in HUVECs were upregulated, while the level of miR-19b-3p was downregulated. Knockdown of MALAT1 with siRNA significantly reduced the HIF-1α level induced by HYP. In addition, MALAT1 knockdown inhibited HYP-induced HUVECs apoptosis, autophagy and inflammation. The overexpression of HIF-1α overcame the effect of MALAT1 knockdown. Mechanism analysis showed that MALAT1-targeted miR-19b-3p and then regulated downstream HIF-1α. MALAT1 knockdown increased the level of miR-19b-3p in cells, and increased miR-19b-3p further inhibited the expression of HIF-1α, thereby reducing the HYP-induced HUVECs apoptosis, autophagy and inflammation. Taken together, these results suggest that MALAT1 may be a potential target for mitigating HYP-induced endothelial cell injury.

Silencing of long non-coding RNA MALAT1 suppresses inflammation in septic mice: role of microRNA-23a in the down-regulation of MCEMP1 expression.

OBJECTIVE: Sepsis is a life-threatening disease without ideal biomarkers. Some long non-coding RNAs (lncRNAs) are found to be implicated in sepsis. Thus, we investigated the effects of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on inflammation in septic mice and the potential mechanisms of the MALAT1/microRNA-23a (miR-23a)/MCEMP1 axis. METHODS: The sepsis mice model was generated by cecal ligation and puncture (CLP). Then the expressions of lncRNA MALAT1, mast cell-expressed membrane protein 1 (MCEMP1), and miR-23a in septic mice were determined. The interaction between lncRNA MALAT1, miR-23a and MCEMP1 was confirmed. Loss- and gain-of-function approaches were used to verify the roles of the lncRNA MALAT1, miR-23a, and MCEMP1 in inflammation, cell proliferation and apoptosis in septic mice. RESULTS AND CONCLUSION: The myeloperoxidase (MPO) activity and the expression of interleukin 6 (IL-6), IL-1ß, IL-10, and tumor necrosis factor-α (TNF-α) were detected. High expression of the lncRNA MALAT1 and MCEMP1, as well as low expression of miR-23a, was observed in septic mice. LncRNA MALAT1 competitively bound to miR-23a, and miR-23a targeted MCEMP1. Moreover, the down-regulation of lncRNA MALAT1 repressed the expression of MPO, IL-6, IL-10, TNF-α, and IL-1ß. Silencing of lncRNA MALAT1 or overexpression of miR-23a reduced inflammation, inhibited cell proliferation, and promoted cell apoptosis in septic mice. Taken together, MALAT1 promotes the inflammation in septic mice by binding to miR-23a to up-regulate MCEMP1. Therefore, silencing of lncRNA MALAT1 might provide a novel therapeutic target for sepsis.

Metastasis Associated Lung Adenocarcinoma Transcript 1: An update on expression pattern and functions in carcinogenesis.

The Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is among long non-coding RNAs (lncRNAs) which has disapproved the old term of "junk DNA" which was used for majority of human genome which are not transcribed to proteins. An extensive portion of literature points to the fundamental role of this lncRNA in tumorigenesis process of diverse cancers ranging from solid tumors to leukemia. Being firstly identified in lung cancer, it has prognostic and diagnostic values in several cancer types. Consistent with the proposed oncogenic roles for this lncRNA, most of studies have shown up-regulation of MALAT1 in malignant tissues compared with non-malignant/normal tissues of the same source. However, few studies have shown down-regulation of MALAT1 in breast cancer, endometrial cancer, colorectal cancer and glioma. In the current study, we have conducted a comprehensive literature search and provided an up-date on the role of MALAT1 in cancer biology. Our investigation underscores a potential role as a diagnostic/prognostic marker and a putative therapeutic target for MALAT1.

A genetic variant in the promoter of lncRNA MALAT1 is related to susceptibility of ischemic stroke.

BACKGROUND: Metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) was aberrantly expressed in diverse diseases. Particularly in ischemic stroke (IS), the abnormal expression of MALAT1 played important roles including promotion of angiogenesis, inhibition of apoptosis and inflammation and regulation of autophagy. However, the effects of genetic variation (single nucleotide polymorphisms, SNPs) of MALAT1 on IS have rarely been explored. This study aimed to investigate whether SNPs in promoter of MALAT1 were associated with the susceptibility to IS. METHODS: A total of 316 IS patients and 320 age-, gender-, and ethnicity-matched controls were enrolled in this study. Four polymorphisms in the promoter of MALAT1 (i.e., rs600231, rs1194338, rs4102217, and rs591291) were genotyped by using a custom-by-design 48-Plex SNPscan kit. RESULTS: The rs1194338 C > A variant in the promoter of MALAT1 was associated with the risk of IS (AC vs. CC: adjusted OR = 0.623, 95% CI, 0.417-0.932, P = 0.021; AA vs. CC: adjusted OR = 0.474, 95% CI, 0.226-0.991, P = 0.047; Dominant model: adjusted OR = 0.596, 95% CI, 0.406-0.874, P = 0.008; A vs. C adjusted OR = 0.658, 95% CI, 0.487-0.890, P = 0.007). The haplotype analysis showed that rs600231-rs1194338-rs4102217-rs591291 (A-C-G-C) had a 1.3-fold increased risk of IS (95% CI, 1.029-1.644, P = 0.027). Logistic regression analysis identified some independent impact factors for IS including rs1194338 AC/AA, TC, TG, HDL-C, LDL-C, Apo-A1, Apo-B and NEFA (P < 0.05). CONCLUSIONS: These results suggest that the rs1194338 AC/AA genotypes may be a protective factor for IS.

The clinical value of lncRNA MALAT1 and its targets miR-125b, miR-133, miR-146a, and miR-203 for predicting disease progression in chronic obstructive pulmonary disease patients.

OBJECTIVE: The study aimed to explore the correlations of long non-coding RNA MALAT1 (lncRNA MALAT1) and its targets microRNA (miR)-125b, miR-133, miR-146a, and miR-203 with acute exacerbation risk, inflammation, and disease severity of chronic obstructive pulmonary disease (COPD). METHODS: Plasma samples were obtained from 120 acute exacerbation COPD (AECOPD) patients, 120 stable COPD patients, and 120 healthy controls (HCs). RT-qPCR was conducted to detect lncRNA MALAT1 expression and its target miRNAs, and ELISA was performed to detect the inflammatory cytokines. RESULTS: LncRNA MALAT1 was highest in AECOPD patients followed by stable COPD patients and then HCs, which distinguished AECOPD patients from HCs (AUC: 0.969, 95% CI: 0.951-0.987) and stable COPD patients (AUC: 0.846, 95% CI: 0.798-0.894). Furthermore, lncRNA MALAT1 positively correlated with GOLD stage in both AECOPD and stable COPD patients. Regarding inflammatory cytokines, lncRNA MALAT1 positively correlated with tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, IL-8, IL-17, and IL-23 in both AECOPD and stable COPD patients. Besides, lncRNA MALAT1 negatively correlated with miR-125b, miR-146a, and miR-203 in AECOPD patients and reversely correlated with miR-125b and miR-146a in stable COPD patients. Notably, miR-125b, miR-133, miR-146a, and miR-203 were the lowest in AECOPD patients, followed by stable COPD patients, and then HCs; miR-125b, miR-133, miR-146a, and miR-203 negatively correlated with inflammation and GOLD stage in AECOPD and stable COPD patients. CONCLUSION: LncRNA MALAT1 exhibits clinical implications in acute exacerbation risk prediction and management of COPD via the inner-correlation with its targets miR-125b, miR-146a, and miR-203.

[Relationship between long non-coding RNA MALAT1 and prostate cancer].

Prostate cancer (PCa), as a malignant tumor originating in the prostate glandular epithelium, has become a global "killer" that threatens the health of elderly men. PCa-related studies have been focusing on the progression mechanisms and treatment strategies of the malignancy, particularly on the role of long non-coding RNA (lncRNA) in recent years. The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a key role in the progression and treatment of PCa, as well as in its metastasis and invasion and cell proliferation. lncRNA MALAT1 not only influences the biological characteristics of PCa, but also has a regulatory effect on the medicinal treatment of the disease, its action mechanisms involving ceRNA and AR signaling pathways. This review focuses on the relationship between lncRNA MALAT1 and PCa, aiming to provide a new research direction for the diagnosis and treatment of the malignancy.

Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1/microRNA-202-3p/periostin axis modulates invasion and epithelial-mesenchymal transition in human cervical cancer.

The human cervical cancer (CC) has been identified as one of the most common tumors in women, and the molecular regulation in CC still remains unclear. The dysregulation of periostin has been found in a variety of cancers, but whether it is involved in the regulation of CC is unknown. The present study aimed to investigate the biological roles of periostin in CC and to explore the potential molecular regulation mechanisms. Here we found that the expression of periostin was overexpressed in CC tissues and CC cell lines (HeLa and SiHa). Knockdown of periostin in HeLa or SiHa cells significantly decreased cell viability, cell migration and invasion, and reduced epithelial-mesenchymal transition (EMT). Moreover, periostin knockdown suppressed the activation of Akt/the mammalian target of rapamycin (mTOR) signaling pathway, which is crucial for periostin to regulate the above biological activities in CC cells. Furthermore, we found that the periostin expression was positively correlated with the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and negatively correlated with the expression of microRNA (miR)-202-3p in CC tissues. We confirmed that MALAT1 positively regulated the expression of periostin by negatively modulating miR-202-3p. In addition, the MALAT1/miR-202-3p/periostin axis was deeply associated with the regulation of the cell viability, cell migration and invasion, and EMT in CC cells. Taken together, these findings suggest that periostin, which can be regulated by the MALAT1-miR-202-3p axis, plays an important role in regulating cell viability, cell migration and invasion, and EMT of CC cells via activating Akt/mTOR signaling.

MALAT1 promoted cell proliferation and migration via MALAT1/miR-155/MEF2A pathway in hypoxia of cardiac stem cells.

Accumulating evidence revealed that hypoxia contributed to many human diseases, including ischemic myocardium and heart failure (HF). In recent years, the roles of hypoxia in stem cell survival and cardiac biology have been studied extensively. However, the underlying molecular mechanisms remain to be elucidated. As a leading cause of HF, ischemic heart disease was correlated with hypoxia. In this study, we firstly constructed the hypoxia cell model by CoCl2 in cardiac stem cells (CSCs) and found that hypoxia induced the cell proliferation and migration potential in CSCs. Then, we demonstrated that the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was promoted in CoCl2 -induced CSCs hypoxia model. Furthermore, we found that knockdown of MALAT1 inhibited the cell proliferation and migration in CoCl2 -induced CSCs hypoxia model. In addition, we revealed that MALAT1 regulated the microRNA-155 (miR-155) expression in CSCs under both the normal and hypoxia conditions and further, manipulation of the miR-155 expression affected the role of MALAT1 in CoCl2 -induced CSCs hypoxia cell model. We then illustrated that miR-155 regulated the myocyte enhancer factor 2A (MEF2A) expression in CSCs under both the normal and hypoxia conditions and further, changing the expression of MEF2A affected the role of miR-155. Finally, we demonstrated that MALAT1 regulated the MEF2A expression and exerted its role via modulation of the MALAT1/miR-155/MEF2A pathway. Taken together, our study illustrated that MALAT1 promoted the cell proliferation and migration in CoCl2 -induced CSCs hypoxia model, acting mechanistically by promoting MEF2A expression via "sponging" miR-155.

Administration of resveratrol improved Parkinson's disease-like phenotype by suppressing apoptosis of neurons via modulating the MALAT1/miR-129/SNCA signaling pathway.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in the pathogenesis of Parkinson's disease (PD). In addition, resveratrol was shown to regulate the expression of MALAT1. Therefore, the objective of this study was to clarify the role of resveratrol in PD. During the study, luciferase assays were conducted to determine the effect of resveratrol on the transcription efficiency of MALAT1 promoter as well as the regulatory relationships among MALAT1, miR-129, and SNCA. In addition, real-time PCR, Western blot analysis, MTT and flow cytometry analyses were conducted to investigate the mechanism of resveratrol in PD. Furthermore, a PD mouse model was established to study the role of resveratrol in vivo. It was found that resveratrol increased the number of TH+ cells and the expression of miR-129, while decreasing the expression of MALAT1 and SNCA. In addition, MALAT1 inhibited the expression of miR-129, a negative regulator of SNCA, thus increasing the expression of SNCA. A further mechanistic study revealed that resveratrol inhibited MALAT1 expression by blocking the transcription of the MALAT1 promoter. Finally, MPTP treatment could decrease cell proliferation and increase cell apoptosis, while resveratrol could partly offset the effect of MPTP. In summary, the therapeutic effect of resveratrol in the treatment of PD can be attributed to its ability to modulate the MALAT1/miR-129/SNCA signaling pathway.