Metastasis-associated Lung Adenocarcinoma Transcript 1 Gene Research Articles

Investigation of the expression of long non-coding RNA in Parkinson’s disease

BackgroundParkinson’s disease is the second most common age-related neurodegenerative disease after Alzheimer’s. Pathogenic factors in Parkinson’s include inflammation and oxidative stress, which lead to dopaminergic cell apoptosis. The case–control study aims to determine the expression level of long non-coding RNAs (lncRNAs) of the apoptosis pathway in Parkinson’s patients compared to healthy individuals. In the case–control study, 50 patients with Parkinson’s disease were examined, along with 50 healthy individuals matched in age and sex. In both groups, the expression of long non-coding RNAs, including taurine upregulated 1 (TUG1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), nuclear-enriched abundant transcript 1 (NEAT1), and growth arrest-specific 5 (GAS5), was compared using real-time polymerase chain reaction (PCR).ResultsThe ratio of MALAT1, NEAT1, and TUG1 gene expression in the case group was statistically significantly higher than in healthy individuals. The ratio of GAS5 gene expression in people with Parkinson’s disease was lower, with a statistically significant difference. The ratio of HULC gene expression was higher in the case group, but it did not show a statistically significant difference with the control group.ConclusionThe involvement of long lncRNAs that increase apoptosis may play a role in the pathogenesis of the disease, which may be used for identification and therapeutic purposes.

Expression Analysis of Long Noncoding RNA-MALAT1 and Interleukin-6 in Inflammatory Bowel Disease Patients.

Inflammatory bowel disease (IBD) manifests as chronic inflammation within the gastrointestinal tract. The study focuses on a long noncoding RNA (lncRNA) known as Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). MALAT1's misregulation has been linked with various autoimmune diseases and regulates proinflammatory cytokines. The role of IL6 in immune-triggered conditions, including IBD, is another focal point. In this research, the expression of MALAT1 and IL6 in IBD patients was meticulously analyzed to uncover potential interactions. The study involved 33 IBD patients (13 with Crohn's disease and 20 with ulcerative colitis) and 20 healthy counterparts. Quantitative real-time polymerase chain reaction determined the MALAT1 and IL6 gene expression levels. The competitive endogenous RNA (ceRNA) regulatory network was constructed using several tools, including LncRRIsearch and Cytoscape. A deep dive into the Inflammatory Bowel Disease database was undertaken to understand IL6's role in IBD. Drugs potentially targeting these genes were also pinpointed using DGIdb. Results indicated a notable elevation in the expression levels of MALAT1 and IL6 in IBD patients versus healthy controls. MALAT1 and IL6 did not show a direct linear correlation, but IL6could serve as MALAT1's target. Analyses unveiled interactions between MALAT1 and IL6, regulated by hsa-miR-202-3p, hsa-miR-1-3p, and has-miR-9-5p. IL6's pivotal role in IBD-associated inflammation, likely interacting with other cytokines, was accentuated. Moreover, potential drugs like CILOBRADINE for MALAT1 and SILTUXIMAB for IL6 were identified. This research underscored MALAT1 and IL6's potential value as targets in diagnosis and treatment for IBD patients.

Long non-coding RNAs TUG1 and MEG3 in patients with type 2 diabetes and their association with endoplasmic reticulum stress markers.

Long non-coding RNAs (lncRNAs), including taurine upregulated gene 1 (TUG1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and maternally expressed 3 (MEG3) play a regulatory role in endoplasmic reticulum (ER) stress. The present study aimed to investigate the expression of these lncRNAs in patients with type 2 diabetes and their association with biochemical and ER stress parameters. Participants included 57 patients with diabetes and 32 healthy individuals. Real-time PCR was performed to assess MALAT1, TUG1, MEG3, ATF4, and CHOP gene expression in peripheral blood mononuclear cells. Plasma GRP78, advanced glycation end products (AGEs), and insulin were measured using enzyme-linked immunosorbent assay (ELISA), and insulin resistance (IR) was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR). The expression of TUG1, MEG3, ATF4, and CHOP genes was significantly increased in the patients with diabetes compared to healthy individuals. MALAT1 gene expression was also higher in patients group; although it did not reach significant levels. TUG1 and MEG3 expression revealed significant positive correlations with the indices of glycemic control, including FBS, HbA1c, HOMA-IR, and AGEs, as well as markers of ER stress. MALAT1 expression was also positively correlated with ATF4 and AGEs. The expression levels of TUG1 and MEG3 lncRNAs were increased in patients with diabetes and were associated with glycemic control and components of ER stress. Thus, these lncRNAs might be considered appropriate markers to identify ER stress due to hyperglycemia.

MALAT1 Polymorphisms and Lung Cancer Susceptibility in a Chinese Northeast Han Population.

Background: LncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was competitive endogenous RNA (ceRNA) involved in various molecular processes for metastasis development in lung cancer. Single nucleotide polymorphisms (SNPs) in MALAT1 gene might be predictive markers for lung cancer. In our study, we selected rs619586 and rs3200401 in MALAT1 gene to explore their effects on lung cancer susceptibility.Methods: The case-control study included 444 lung cancer cases and 460 healthy controls. Genotyping was performed by Taqman allelic discrimination method. Logistic regression, Student t-test, and Chi-square test (χ2) were used to analyze the data.Results: The findings of the study showed that rs3200401 was significantly associated with the risk of non-small cell lung cancer (NSCLC) and lung squamous cell carcinoma (LUSC). Compared with homozygous CC genotype, CT heterozygous genotype decreased risk of NSCLC (Pa = 0.034) and LUSC (Pa = 0.025). In addition, no statistical association was detected between rs619586 and lung cancer susceptibility. The interactions between genes and cigarette smoking were discovered via crossover analysis. However, there were no remarkable gene-environment interactions in additive and multiplicative model.Conclusion: Rs3200401 in lncRNA MALAT1 was associated with the susceptibility of non-small-cell lung cancer and lung squamous cell carcinoma. The gene-environmental (cigarette smoking) interactions were not notable.

Association of MALAT-1 gene single nucleotide polymorphisms with genetic susceptibility to systemic lupus erythematosus.

Background: Abnormal expression and function of long non-coding RNAs (lncRNAs) are closely related to the pathogenesis of systemic lupus erythematosus (SLE). In this study, we aimed to investigate the association of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) gene single-nucleotide polymorphisms (SNPs) with susceptibility and clinical characteristics of SLE patients. Methods: A case-control study including 489 SLE patients and 492 healthy controls was conducted. Four MALAT-1 SNPs (rs4102217, rs591291, rs11227209, and rs619586) were genotyped in all subjects, their correlation with SLE susceptibility and clinical characteristics were also analyzed. Results: Results showed that the rs4102217 locus was associated with the risk of SLE. In recessive models, the GG+CG genotype of rs4102217 was associated with the decreased risk of SLE compared to CC (p = 0.036, OR = 0.348, 95% CI: 0.124-0.975). In additive models, the GG genotype of rs4102217 was associated with the decreased risk of SLE compared to CC (p = 0.040, OR = 0.355, 95% CI: 0.127-0.996). However, no association was found between MALAT-1 gene polymorphism and clinical manifestations of SLE (all p > 0.05). Conclusion: In summary, MALAT-1 rs4102217 is associated with susceptibility to SLE, suggesting that MALAT-1 may play a role in SLE.

Combined Impacts of Genetic Variants of Long Non-Coding RNA MALAT1 and the Environmental Carcinogen on the Susceptibility to and Progression of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the oral cavity, and long non-coding (lnc)RNA of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was recently reported to play a crucial role in OSCC development and progression. However, potential effects of genetic variants of MALAT1 on the development of OSCC are still unclear. Herein, we performed a case-control study in 1350 patients with OSCC and 1199 healthy controls to evaluate the association between functional single-nucleotide polymorphisms (SNPs) of MALAT1 and OSCC susceptibility, as well as its clinicopathologic characteristics. A TaqMan allelic discrimination assay was used to genotype four tagging SNPs, viz., rs3200401 C>T, rs619586 A>G, rs1194338 C>A, and rs7927113 G>A, and results showed that the MALAT1 rs3200401 T allele had a lower risk of OSCC (adjusted odds ratio (AOR): 0.779, 95% confidence interval (CI): 0.632~0.960, p=0.019) and a higher risk of developing moderately (grade II)/poorly (grade III) differentiated OSCC (AOR: 1.508-fold, 95% CI: 1.049~2.169, p=0.027) under a dominant model. According to environmental carcinogen exposure, patients with a betel quid-chewing habit who carried the T allele of rs3200401 more easily developed high-grade (II/III) OSCC (AOR: 1.588, 95% CI: 1.055~2.390, p=0.027), and patients with the same genotype but who did not chew betel quid had a lower risk of developing lymph node metastasis (AOR: 0.437, 95% CI: 0.255~0.749, p=0.003). In addition to rs3200401, the rs619586 AG/GG genotype was associated with increased risks of developing advanced stages (III+IV) and larger tumor sizes (>T2) compared to the AA genotype, especially in the subgroup of betel quid chewers. Furthermore, analyses of clinical datasets revealed that the MALAT1 expression level was upregulated in OSCC compared to normal tissues, especially in the betel quid-chewing population. These results indicated involvement of MALAT1 SNPs rs3200401 and rs619586 in the development of OSCC and support the interaction between MALAT1 gene polymorphisms and the environmental carcinogen as a predisposing factor for OSCC progression.

MALAT1 gene rs600231 polymorphism positively associated with acute coronary syndrome in Chinese population: a case-control study

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been recognized as a major player in the pathogenesis of coronary artery disease (CAD). The aim of the study was to determine the association between polymorphisms of the MALAT1 gene and acute coronary syndrome (ACS) in a Chinese population in Xinjiang. In the case-control study, we genotyped three nucleotide polymorphisms (rs3200401, rs4102217, rs600231) of the MALAT1 gene using SNPscanTM typing assays (1,053 controls and 929 ACS patients). Furthermore, we explored a predictive model using MALAT1 rs600231 and clinical variables to predict the risk of ACS. Finally, the relative expression of long noncoding RNA (lncRNA) MALAT1 was also measured in 92 ACS patients and 92 controls using quantitative real-time polymerase chain reaction (qRT-PCR). The prevalence of the GG genotype of rs600231 in ACS group was higher than that in control group (15.7% vs. 14.7%, P=0.048). The dominant model differed (AG + GG vs. AA) and the G allele of rs600231 in ACS group was higher than that in control group (for dominant model: 66.2% vs. 60.9%, P=0.014; for allele: 41.0% vs. 37.8%, P=0.042). Multivariate logistic regression analysis and the predictive nomogram model showed that the dominant model of rs600231 remained an independent risk factor for ACS [odds ratio (OR) =1.32, 95% confidence interval (CI): 1.07-1.63, P=0.009]. The area under the receiver operating characteristic (ROC) curve (AUC) for the nomogram model for the prediction of ACS was 0.738 (95% CI: 0.716-0.761). In addition, in the AG and GG phenotypes, the relative expression of lncRNA MALAT1 was significantly higher in ACS patients than in controls with the same phenotypes (P<0.05). Among ACS group, compared to other genotype carriers, the relative expression level of MALAT1 in GG genotype carriers was higher (P<0.05). The present study suggested that the AG and GG genotype of rs600231 in MALAT1 gene was independently associated with ACS, and could be a risk genetic marker of ACS in a Chinese population in Xinjiang.

Association of MALAT1 expression in gastric carcinoma and the significance of its clinicopathologic features in an Iranian patient.

The aim of this study was to evaluate the expression of MALAT1 and the relationship between its expression with clinical characteristics in an Iranian gastric cancer patient. Long non-coding RNAs (LncRNAs) play critical roles in the initiation and development of gastric cancer. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved lncRNA and plays key roles in various types of human cancer. However, our understanding of the role of lncRNAs in the occurrence and development of gastric cancer is not fully clear. This cross-sectional study was performed on 41 gastric tumor tissue samples with matched normal adjacent tumor tissues. The RNA level of lncRNA MALAT1 gene was assessed using quantitative Real-time polymerase chain reaction. B2M was used as an internal control. The 2 -ΔΔCq method was adopted to determine expression fold changes. A significant association was observed between the levels of MALAT1 in gastric tumor tissues compared with normal adjacent tissues (mean= 1.558, p= 0.014). In addition, clinicopathologic data on MALAT1 RNA expression levels in gastric cancer tissues was evaluated. No significant association was observed between the relative expression of MALAT1 and the stage, grade, H. pylori infection, and tumor size groups among gastric cancer patients (p= 0.82, p= 0.904, p= 0.407, and p= 0.701, respectively). The current results showed that MALAT1 has a significant association in gastric cancer. The expression of MALAT1 may be used as a diagnostic biomarker for monitoring gastric cancer patients.

MicroRNA Binding Site Polymorphisms of the Long-Chain Noncoding RNA MALAT1 are Associated with Risk and Prognosis of Colorectal Cancer in Chinese Han Population

Background: The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) gene's rs664589 locus is located within the binding site of the miRNA hsa-miR-194-5p for its cognate long-chain noncoding RNA (lncRNA) MALAT1. The aim of this study was to investigate the association between the rs664589 single nucleotide polymorphism (SNP) and the risk and prognosis of colorectal cancer (CRC) in the Chinese Han population. Methods: A cohort of 340 patients with CRC who underwent surgical resection and another group of 340 healthy subjects were enrolled in this study and analyzed for their rs664589 genotypes. In addition, quantitative real-time-polymerase chain reaction was used to detect the expression levels of the lncRNA MALAT1 and the hsa-miR-194-5p in cancer tissues and paracancerous normal tissues of CRC patients. Results: The risk of CRC in subjects carrying the G allele at the rs664589 locus in the 3' untranslated region of the MALAT1 gene was 1.81 times higher than for C allele carriers. The expression levels of the lncRNA MALAT1 in cancer tissues was significantly higher than that in paracancerous tissues, while the hsa-miR-194-5p expression level was significantly lower in cancerous tissues compared to cognate paracancerous tissues. The progression-free survival (PFS) rate for patients with the MALAT1 gene rs664589 locus GG genotype was significantly lower than that of CG genotype patients. Moreover, lncRNA MALAT1 inhibited the expression of hsa-miR-194-5p. Conclusion: The risk of CRC was relatively higher among MALAT1 rs664589 G allele carriers, and the CRC patients with a G allele had a lower PFS. The likely mechanism underlying these observations is that the rs664589 SNP affects the binding efficiency between the lncRNA MALAT1 and the miRNA has-miR-194-5p, although this awaits laboratory confirmation.

MiR-146b-5p Regulates the Expression of Long Noncoding RNA MALAT1 and Its Effect on the Invasion and Proliferation of Papillary Thyroid Cancer.

Background: The incidence of thyroid cancer has increased dramatically in recent decades due, in large part, to identifications of subclinical diseases. Literature on thyroid cancer has examined the pathogenesis of high invasive papillary thyroid cancer (PTC) and has improved the prevention and treatment of PTC. This study aims to investigate the effects of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on PTC migration and invasion, and clarify the regulatory mechanisms between miR-146b-5p and MALAT1. Materials and Methods: In this study, we examined the differential expression of MALAT1, miR-146b-5p, and DNA methyltransferases 3A (DNMT3A) in PTC tissues. The effect of MALAT1 on the proliferation and invasion ability of PTC cells was verified by constructing a sh-MALAT1 knockdown cell model. Correlations between MALAT1, miR-146b-5p, and DNMT3A were analyzed by the Pearson correlation method. Finally, we verified the regulatory relationship between miR-146b-5p and MALAT1 by the luciferase assay and rescue assay. Results: The expression of MALAT1 was upregulated in PTC tissues and cells, while a MALAT1 knockdown counteracted cellular activity, migration, and invasion of B-CPAP and K1 cells. The relationship between miR-146b-5p and DNMT3A was negative, while the relationship between miR-146b-5p and MALAT1 was positive. Both genes were separately detected using the Pearson correlation method. The luciferase assay and rescue assay demonstrated that a binding site in miR-146b-5p was existent in the 3' untranslated region of DNMT3A, while a knockdown of DNMT3A partially rescued si-miR-146b-5p induced proliferation, migration, and invasion effects on PTC cells. Conclusions: The MALAT1 gene is highly expressed in PTC, while the knockdown MALAT1 gene attenuates the cellular activity and invasive ability of PTC cells. The microRNA miR-146b-5p can promote a MALAT1 expression by negatively regulating DNMT3A in PTC.

Association of lncRNA-p53 regulatory network (lincRNA-p21, lincRNA-ROR and MALAT1) and p53 with the clinicopathological features of colorectal primary lesions and tumors.

Colorectal cancer (CRC) is a common intestinal cancer with a high mortality rate. Early detection of this type of cancer is fundamental to the prevention of the disease, which results in improved survival rates. In the human colon tissue, transition from normal epithelium to adenoma is considered to be caused by unknown molecular incidents occurring over 5–10 years. The detection of CRC has proved problematic when in the early stages of disease. In addition, identifying suitable biomarkers for the detection of CRC progress in patients remains one of the most significant challenges. Long non-coding RNAs have been demonstrated to contribute to the promotion of CRC. The aim of the present study was to investigate the clinical and biological significance of long intergenic non-coding (linc)RNA-p21, lincRNA-regulator of reprogramming (ROR) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the colon tumor and polyp tissue, and the association that these have with the expression of p53 at the mRNA level. Neoplastic and paired adjacent normal tissue samples were obtained from 72 patients (46 polyps and 26 tumors). Reverse transcription-quantitative PCR was performed to determine the relative fold changes in the expression of lincRNA-p21, lincRNA-RoR, MALAT1 and p53 in the samples. A significant association was observed between the levels of MALAT1 and p53 in neoplasm tissues (R=0.073; P<0.05). The relative expression of the MALAT1 gene revealed a statistically significant difference between the different polyp types and number of polyps (P=0.0028 and 0.022, respectively). Adjuvant therapy in patients with tumors revealed an association between the levels of lincRNA-ROR and lincRNA-p21 expression (P=0.015 and 0.038, respectively). MALAT1 may be selected as an early detection biomarker for CRC. Furthermore, lincRNA-ROR and lincRNA-p21 may serve as prognostic and therapeutic biomarkers in patients with CRC.

Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1.

Colorectal cancer (CRC) is the third most common tumor in the world; however, the role and mechanism of endoplasmic reticulum (ER) stress in CRC metastasis remains largely unclear. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA), which has previously been associated with CRC metastasis. It has been suggested that ER stress pathways regulate lncRNA expression; however, the effect of ER stress on MALAT1 expression in cancer is unknown. The present study aimed to investigate the relationship between ER stress pathways, MALAT1 expression and cell migration in CRC cells. ER stress was induced by thapsigargin (TG); low dose TG induced the migration of HT29 and HCT116 cells, but not SW1116 and SW620 cells. This effect was associated with increased expression levels of MALAT1, as the knockdown of MALAT1 prevented TG-induced cell migration. TG-induced MALAT1 expression was associated with inositol-requiring enzyme 1 (IRE1) expression and activation of the protein kinase R (PKR)-like ER kinase (PERK) signaling pathway. X-box-binding protein 1 (XBP1) and activating transcription factor 4 (ATF4) binding sites were predicted to be located in the MALAT1 gene promoter regions and the expression of MALAT1 was positively associated with XBP1 and ATF4 expression levels in CRC tissue samples. Thus, these findings indicated that ER stress may promote the migration of CRC cells and contribute to the progression of CRC through the activation of the IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways. In conclusion, to the best of our knowledge, this study is the first report that lncRNA MALAT1 expression is regulated by the IRE1/XBP1 pathway in CRC.

Hypoxia induces cancer cell-specific chromatin interactions and increases MALAT1 expression in breast cancer cells

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA overexpressed in various cancers that promotes cell growth and metastasis. Although hypoxia has been shown to up-regulate MALAT1, only hypoxia-inducible factors (HIFs) have been implicated in activation of the MALAT1 promoter in specific cell types and other molecular mechanisms associated with hypoxia-mediated MALAT1 up-regulation remain largely unknown. Here, we demonstrate that hypoxia induces cancer cell-specific chromatin-chromatin interactions between newly identified enhancer-like cis-regulatory elements present at the MALAT1 locus. We show that hypoxia-mediated up-regulation of MALAT1 as well as its antisense strand TALAM1 occurs in breast cancer cells, but not in nontumorigenic mammary epithelial cells. Our analyses on the MALAT1 genomic locus discovered three novel putative enhancers that are located upstream and downstream of the MALAT1 gene body. We found that parts of these putative enhancers are epigenetically modified to a more open chromatin state under hypoxia in breast cancer cells. Furthermore, our chromosome conformation capture experiment demonstrated that noncancerous cells and breast cancer cells exhibit different interaction profiles under both normoxia and hypoxia, and only breast cancer cells gain specific chromatin interactions under hypoxia. Although the HIF-2α protein can enhance the interaction between the promoter and the putative 3' enhancer, the gain of chromatin interactions associated with other upstream elements, such as putative -7 and -20 kb enhancers, were HIF-independent events. Collectively, our study demonstrates that cancer cell-specific chromatin-chromatin interactions are formed at the MALAT1 locus under hypoxia, implicating a novel mechanism of MALAT1 regulation in cancer.

Transcript-level regulation of MALAT1-mediated cell cycle and apoptosis genes using dual MEK/Aurora kinase inhibitor "BI-847325" on anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is the most lethal malignancy in thyroid carcinomas. Long non-coding RNAs (lncRNAs) are a member of non-coding RNAs, regulating the expression of gene. Metastasis-associated lung adenocarcinoma transcript1 (MALAT1) is an onco-lncRNA that is overexpressed in several carcinomas including ATC. Evidence showed that MALAT1 has a crucial function in apoptosis, and cell cycle progression. In order to take advantage of 3D cell culture system in cancer investigation, we have used a 3D in vitro ATC model to determine the effect of dual MEK/Aurora kinase inhibitor BI-847325 anticancer drug on the fundamental molecular mechanisms of MALAT1-mediated gene regulation in ATC. In this study, ATC cell lines (C643 and SW1736) were grown in alginate scaffold. Encapsulated cells were treated by BI-847325. Changes in expression of MALAT1, Mcl1, miR-363-3p, and cyclinD1 were measured by qRT-PCR. MALAT1 gene expression following BI-847325 treatment was significantly downregulated in C643 and SW1736 cell lines. Reversely, miR-363-3p expression was significantly upregulated by BI-847325 in both ATC cell lines. Mcl1 expression was significantly downregulated after treatment in C643 cell lines. Moreover, the expression of this gene was not significantly reduced following BI-847325 treatment in SW1736 cell line. Additionally, cyclin D1 expression was significantly downregulated after treatment in both ATC cell lines. Altogether, the result of this study was the first report of MALAT1's molecular function in ATC and suggested that BI-847325 which inhibits both MEK and Aurora kinase family could be effective against ATC by regulating the genes involved in cell cycle and apoptosis including MALAT1and its downstream genes. Graphical abstract Schematic representation of the biological role of MALAT1 in cyclin D1, miR-363-3p and Mcl1 gene regulations. Stimulation of receptor tyrosine kinase (RTK) by growth factors (GFs) phosphorylates RAS that subsequently activates RAF. Then, RAF phosphorylates MEK. Consequently, activated MEK phosphorylates ERK downstream effector, leading to the MALAT1 gene expression. MALAT1 is a negative regulator of Mcl1 mRNA by sponging of miR-363-3p. In addition, MALAT1 leads to Axin1 and APC downregulation and Wnt/β-catenin signaling pathway activation. Stable β-catenin translocates from the cytoplasm to the nucleus and promotes cyclin D1 gene expression.

Association of polymorphisms in MALAT1 with the risk of esophageal squamous cell carcinoma in a Chinese population.

ObjectiveThe main aim of this study was to investigate the association of polymorphisms in long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) with the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese population.MethodsA total of 245 ESCC patients and 490 gender- and age-matched cancer-free controls were genotyped for four tag single nucleotide polymorphisms (SNPs) of MALAT1 (rs3200401 C > T, rs1122709 C > G, rs664589 C > G, and rs619586 A > G). Statistical analyses including chi-squared test and logistic regression were performed to identify the association between the tag SNPs and risk of ESCC, and false discovery rate (FDR) <25% was applied to adjust for multiple comparisons.ResultsWe found that rs3200401 C > T polymorphism of MALAT1 was significantly associated with increased risk of ESCC (CT vs CC: adjusted OR =1.59, 95% CI =1.07–2.35, P=0.021; TT vs CC: adjusted OR =2.27, 95% CI =1.04–4.96, P=0.039; dominant model [CT+TT vs CC]: adjusted OR =1.68, 95% CI =1.16–2.43, P=0.006). In the stratified analysis, rs3200401 TT and CT/TT genotypes were associated with increased risk of ESCC compared with CC genotype in subgroup of never drinking (TT vs CC: adjusted OR =2.34, 95% CI =1.02–5.34, P=0.044; CT/TT vs CC: adjusted OR =1.52, 95% CI =1.02–2.26, P=0.041). However, compared with AA genotype, MALAT1 rs619586 GG was associated with decreased risk of ESCC in ever drinking subgroup (GG vs AA: adjusted OR =0.38, 95% CI =0.15–0.99, P=0.049). The results remained significant after FDR adjustment (FDR value <0.25) except for the comparison between rs619586 GG and AA genotype in ever drinking subgroup.ConclusionTaken together, our findings proposed that polymorphism rs3200401 C > T in MALAT1 gene is associated with increased risk of ESCC. Since the association between rs619586 A > G polymorphism and ESCC risk was not significant after FDR adjustment, there was a minor possibility that rs619586 A > G might be a protective factor for ESCC.

LncRNA MALAT1 gene polymorphisms in coronary artery disease: a case-control study in a Chinese population.

Background: Coronary artery disease (CAD) is one of the main fatal diseases all over the world. CAD is a complex disease, which has multiple risk factors mechanisms. In recent years, genome-wide association study (GWAS) had revealed single nucleotide polymorphism genes (SNPs) which were closely related with CAD risks. The relationship between long non-coding RNA (lncRNA) MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and CAD risk is largely unknown. To our knowledge, this is the first study which demonstrated the interaction effects of SNP–SNP and SNP–environment with CAD risk. In general, our case–control study is to detect the association between MALAT1 (rs619586, rs4102217) SNPs and CAD risk. Methods: Three hundred and sixty-five CAD patients and three hundred and eighty-four matched control participants blood samples were collected in Liaoning province, China. Two polymorphisms (rs619586, rs4102217) in lncRNA MALAT1 were genotyped by KASP platform. Results: In a stratified analysis, we found that non-drinkers with GC genotype and the recessive model of rs4102217 had higher CAD risk (P=0.010, odds ratio (OR): 1.96, 95% confidence interval (CI) = 1.17–3.28; P=0.026, OR: 1.73, 95% CI = 1.07–2.79) and diabetes mellitus (DM) history group (P=0.010, OR: 4.07, 95% CI = 1.41–11.81; P=0.019, OR: 3.29, 95% CI = 1.22–8.88). In SNP–SNP interactions analysis between MALAT1 and CAD risk, we found rs4102217 had an increase in smokers (GG: OR: 2.04, 95% CI = 1.42–2.92; CC+GC: OR: 2.64, 95% CI = 1.64–4.26) and a decrease in drinkers (CC+GC: OR: 0.33, 95% CI = 0.20–0.55). Smokers with MALAT1 rs619586 AA genotype (OR: 2.20, 95% CI = 1.57–3.07) and GG+AG genotype (OR: 2.11, 95% CI = 1.17–3.81) had a higher risk of CAD. Moreover, drinkers with AA genotype (OR: 0.22, 95% CI = 0.10–0.48) and GG+AG genotype (OR: 0.38, 95% CI = 0.22–0.65) had a lower risk of CAD. According to the MDR software, MALAT1 rs4102217 polymorphism-smoking-drinking was the best interaction model, which has higher risk of CAD (Testing Bal.ACC. = 0.6979). Conclusion: Our study demonstrated that the GC genotype and the recessive model of rs4102217 potentially increased CAD risk in some specific group.

MALAT1 Up-Regulator Polydatin Protects Brain Microvascular Integrity and Ameliorates Stroke Through C/EBPβ/MALAT1/CREB/PGC-1α/PPARγ Pathway.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA contributing to protect the blood-brain barrier (BBB) after stroke. We searched for small molecules that may up-regulate MALAT1 and focused on polydatin (PD), a natural product, as a possible candidate. PD enhanced MALAT1 gene expression in rat brain microvascular endothelial cells, reducing cell toxicity and apoptosis after oxygen and glucose deprivation (OGD). These effects correlated with reduction of inflammatory factors and enhancement of expression of BBB markers. We found opposite changes after MALAT1 silencing. We determined that C/EBPβ is a key transcription factor for PD-mediated MALAT1 expression. PPARγ activity is involved in MALAT1 protective effects through its coactivator PGC-1α and the transcription factor CREB. This suggests that PD activates the MALAT1/CREB/PGC-1α/PPARγ signaling pathway to protect endothelial cells against ischemia. PD administration to rats subjected to brain ischemia by transient middle cerebral artery occlusion (tMCAO) reduced cerebral infarct volume and brain inflammation, protected cerebrovascular endothelial cells and BBB integrity. These effects correlated with increased expression of MALAT1, C/EBPβ, and PGC-1α. Our results strongly suggest that the beneficial effects of PD involve the C/EBPβ/MALAT1/CREB/PGC-1α/PPARγ pathway, which may provide a novel therapeutic strategy for brain ischemic stroke.

Evaluation of MALAT1 promoter DNA methylation patterns in early colorectal lesions and tumors.

This study set out to determine the effect of methylation on MALAT1 gene in primary colorectal lesions and tumors to gain further knowledge about the diagnostic and prognostic value of MALAT. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is one of the long non-coding RNAs that plays an important role in invasion, cell proliferation, and metastasis of various cancers. However, there is insufficient information on the association between MALAT1 and the methylation process as well as its role in the development of colorectal cancer. Methylation pattern of MALAT1 promoter was determined by Methylation-Specific Polymerase Chain Reaction (MSP) in 86 colorectal primary lesions, tumors, and normal specimens. MALAT1 methylation pattern was compared in tumor and polyp tissue. In order to obtain more accurate results, we investigated the association between MALAT1 promoter methylation pattern and clinicopathologic factors in patients. The results indicated that the MALAT1 promoter methylation pattern in the tumor tissue, primary lesion tissue, and normal was not significantly different (p=0.430). Comparison of the MALAT1 promoter methylation pattern between polyp types and tumor tissue groups was not significant either (p=0.437). Surprisingly, the methylation frequency of MALAT1 methylation was significantly higher in colon lesions than in their rectum lesion (p = 0.035). In addition, no significant hypermethylation of MALAT1 was observed between the other patients' clinicopathological data in both polyp 46/66 and tumor tissues 20/66. This study dealt with determining the effect of methylation on MALAT1 gene in primary colorectal lesions and tumors to gain further knowledge about the diagnostic and prognostic value of MALAT.

The long non-coding RNA MALAT1 promotes ovarian cancer progression by regulating RBFOX2-mediated alternative splicing.

Ovarian cancer metastasizes via direct seeding, whereby cancer cells shed from the primary site, resist cell death in the peritoneal cavity, then metastasize to peritoneal organs. We sought to identify molecular mechanisms that facilitate ovarian cancer cell anchorage independent survival. Gene expression profiling was performed on ovarian cancer cells grown in attached or forced suspension culture and confirmed by RT-qPCR. Anoikis was measured by Caspase 3/7 assay. Since the long non-coding RNA Metastasis Associated Lung Adenocarcinoma transcript 1 (MALAT1) was among the transcripts most highly increased in forced suspension culture, modified anti-sense oligonucleotides (ASO) were used to inhibit its expression. Knockdown of RBFOX2 and KIF1B was performed using shRNAs. Publically available datasets were analyzed for association of MALAT1 gene expression with clinicopathological variables. In multiple anoikis-resistant ovarian cancer cell lines MALAT1 expression increased after 24 and 48 h in forced suspension culture compared to attached culture. High MALAT1 is associated with increased stage, recurrence, and reduced survival in ovarian cancer, and in a small percentage of ovarian cancers MALAT1 is amplified. MALAT1 knockdown resulted in decreased proliferation, invasion, anchorage-independent growth, and increased anoikis. Suppression of MALAT1 also resulted in decreased expression of RBFOX2, and alternative processing of the pro-apoptotic tumor suppressor gene KIF1B. RBFOX2 suppression resulted in preferential splicing of the pro-apoptotic isoform of KIF1B (KIFB1B-beta) and increased anoikis. The lncRNA MALAT1 facilitates a pro-metastatic phenotype in ovarian cancer by promoting alternative RNA processing and differential expression of anti-apoptosis and epithelial to mesenchymal transition (EMT)-related genes.

The MALAT1 gene polymorphism and its relationship with the onset of congenital heart disease in Chinese.

Many long non-coding RNAs (lncRNAs), including lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), are involved in various cardiac diseases. We evaluated the effects of tag single nucleotide polymorphisms (tag-SNPs) on MALAT1 gene in a Chinese population of children with congenital heart disease (CHD). In the present study, 713 CHD patients and 730 gender- and age-matched children without CHD were genotyped for MALAT1 tag-SNPs rs11227209, rs619586, and rs3200401. Further investigation of SNP’s function was performed by luciferase assay. Statistical analyses, including uni- and multivariate logistic regression were performed to quantitate the association between these tag SNPs and CHD. We discovered that MALAT1 rs619586 GG allele was significantly associated with lower risk of CHD (odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.59–0.92, P=0.014) in additive model. Functional investigation indicated that G allele of rs619586 could trigger higher expression of MALAT1. We demonstrated that the functional MALAT1 polymorphism rs619586 A>G was significantly associated with CHD susceptibility in Chinese population, potentially via regulating MALAT1 expression.