Metastasis-associated Lung Adenocarcinoma Transcript 1 Silencing Research Articles

Long non-coding RNA MALAT1 regulates oxaliplatin-resistance via miR-324-3p/ADAM17 axis in colorectal cancer cells

BackgroundColorectal cancer (CRC) is one of the most general malignant tumors. Accumulating evidence implied that long non-coding RNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) participated in the tumorigenesis of CRC. However, the effect of MALAT1 in drug-resistance needed to be further illustrated.MethodsLevels of MALAT1, microRNA (miR)-324-3p, and a disintegrin and metalloprotease metallopeptidase domain 17 (ADAM17) were detected using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Cell Counting Kit 8 (CCK-8) was used to assess the half maximal inhibitory concentration (IC50) of oxaliplatin (Ox). Meanwhile, cell proliferation, migration and apoptosis were detected by CCK-8, transwell assay, and flow cytometry, respectively. The interaction between miR-324-3p and MALAT1 or ADAM17 was clarified by dual-luciferase reporter assay. Also, the effect of MALAT1 on tumor growth was detected in xenograft tumor mice treated with Ox.ResultsSignificant up regulation of MALAT1 and ADAM17, and decrease of miR-324-3p were observed in Ox-resistant CRC tissues and cells. MALAT1 deficiency enhanced the sensitivity of Ox-resistant CRC cells response to Ox, while miR-324-3p repression or ADAM17 acceleration could overturn this effect. Moreover, MALAT1 silencing repressed tumor growth in Ox-treated nude mice. Mechanically, MALAT1 exerted promotion effect on the resistance response to Ox via miR-324-3p/ADAM17 axis in Ox-resistant CRC cells.ConclusionMALAT1 modulated the sensitivity of Ox through ADAM17 in Ox-resistant CRC cells by sponging miR-324-3p, thus MALAT1 might serve as a novel insight for the therapy of CRC.

Hyperbaric oxygen-induced long non-coding RNA MALAT1 exosomes suppress MicroRNA-92a expression in a rat model of acute myocardial infarction.

Hyperbaric oxygen (HBO) improves angiogenesis. The effect of HBO on metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1), a pro‐angiogenic long non‐coding RNA, in cardiac myocyte‐derived exosomes and acute myocardial infarction (AMI) is unknown. We aimed to investigate whether MALAT1 is altered in cardiac myocyte‐derived exosomes in response to HBO as well as the molecular regulatory mechanisms of MALAT1 in cardiac myocytes treated with HBO. Cardiac myocytes were cultured, and HBO was applied at 2.5 atmosphere absolute in a hyperbaric chamber. Exosomes were extracted from the culture media. A rat model of AMI generated by the ligation of the left anterior descending artery was used. HBO significantly increased MALAT1 expression in cardiac myocytes and HBO‐induced MALAT1 and exosomes attenuated miR‐92a expression after myocardial infarction. Expression of krüppel‐like factor 2 (KLF2) and CD31 was significantly decreased after infarction and HBO‐induced exosomes significantly reversed the expression. Silencing of MALAT1 using MALAT1‐locked nucleic acid GapmeR significantly attenuated KLF2 and CD31 protein expression after infarction induced by HBO‐induced exosomes. HBO‐induced exosomes also decreased infarct size significantly. HBO‐induced exosomes from cardiac myocytes up‐regulate MALAT1 to suppress miR‐92a expression and counteract the inhibitory effect of miR‐92a on KLF2 and CD31 expression in left ventricular myocardium after myocardial infarction to enhance neovascularization.

MALAT1-mediated recruitment of the histone methyltransferase EZH2 to the microRNA-22 promoter leads to cardiomyocyte apoptosis in diabetic cardiomyopathy

Diabetic patients often have a heightened risk of cardiomyopathy, even in the absence of traditional risk factors such as hypertension and atherosclerotic coronary artery disease. Diabetic cardiomyopathy is characterized by a typical cardiomyopathy specific to diabetes, the pathogenesis of which has yet to be fully elucidated. As a well-documented oncogenic long noncoding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in a variety of pathological processes, including diabetic complications. This study aimed to evaluate the functional roles of MALAT1 in the pathogenesis of diabetic cardiomyopathy. Spontaneously diabetic (db/db) C57BL/Ks mice were employed to establish diabetic cardiomyopathy models in vivo and high glucose (HG)-cultured mouse cardiomyocytes for myocardial damage models in vitro. Mouse left ventricular volume and function were evaluated by echocardiography, while the myocyte cross-sectional area was calculated to evaluate the degree of myocardial hypertrophy. TUNEL staining and flow cytometric analysis were performed to evaluate myocardial damage and cardiomyocyte apoptosis. Silencing of MALAT1 was found to attenuate cardiac dysfunction and inhibit cardiomyocyte apoptosis in db/db mice and HG-cultured mouse cardiomyocytes. MALAT1 recruited the histone methyltransferase EZH2 to the miR-22 promoter region and inhibited its expression. EZH2 induced an increased in the expression of ATP-binding cassette transporter A1 (ABCA1), which was identified to be a target gene of miR-22. Silencing of EZH2 was found to improve cardiac function and prevent cardiomyocyte apoptosis in db/db mice and HG-cultured mouse cardiomyocytes in the presence of MALAT1, suggesting that MALAT1 mediated myocardial damage by recruiting EZH2 to the miR-22 promoter. Taken together, this study's findings provide evidence confirming our hypothesis, suggesting the involvement of MALAT1 in the processes of cardiac function and cardiomyocyte apoptosis via the EZH2/miR-22/ABCA1 signaling cascade, which has potential therapeutic implications for the understanding of diabetic cardiomyopathy.

Downregulation of lncRNA MALAT1 suppresses abnormal proliferation of small intestinal epithelial stem cells through miR‑129‑5p expression in diabetic mice.

The problems caused by diabetes mellitus (DM) and its related complications are gaining increasing attention. In our previous study, the abnormal proliferation of small intestinal epithelial cells (IECs) were observed in diabetic mice. However, little is known regarding the potential underlying mechanism. In the present study, the abnormal proliferation of IECs in DM and the marked upregulation of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was observed. Additionally, knockdown of MALAT1 significantly reduced abnormal IESC proliferation in DM mice. Bioinformatics analysis and luciferase reporter assays revealed that microRNA (miR)‑129‑5p was directly targeted by MALAT1. Moreover, the results of the bioinformatics prediction and luciferase assays demonstrated that MALAT1 directly interacted with SRY‑box 9 (SOX9). Furthermore, MALAT1 silencing was observed to attenuate the abnormal proliferation of IESCs through the SOX9‑mediated WNT/β‑catenin signaling pathway. Knockdown of MALAT1 downregulated SOX9 expression by binding to miR‑129‑5p, thereby inhibiting the abnormal proliferation of IESCs via the WNT/β‑catenin signaling pathway.

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

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. 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. The myeloperoxidase (MPO) activity and the expression of interleukin 6 (IL-6), IL-1β, 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-1β. 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.

Silencing of LncRNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 Inhibits the Proliferation and Promotes the Apoptosis of Gastric Cancer Cells Through Regulating microRNA-22-3p-Mediated ErbB3.

PurposeThis study aimed to investigate the regulatory effects and mechanisms of long non-coding RNA (LncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on gastric cancer (GC) cells.MethodsThe expression of MALAT1 was detected in GC tissues and two GC cell lines (SGC-7901 and BGC-823). MALAT1 was overexpressed and silenced in GC cells by the transfection of pcDNA-MALAT1 and siRNA-MALAT1, respectively. The proliferation and apoptosis of transfected cells, as well as the tumor volume and weight in mice injected with transfected cells were determined. After identifying the interaction between microRNA-22-3p (miR-22-3p) and MALAT1/epidermal growth factor receptor 3 (ErbB3), the effects of miR-22-3p/ErbB3 silencing on the proliferation and apoptosis of GC cells were evaluated.ResultsMALAT1 was significantly upregulated in GC tissues and cells and negatively associated with the survival of GC patients. Overexpression of MALAT1 significantly promoted the proliferation and inhibited the apoptosis of SGC-7901 cells, while silencing of MALAT1 exerts contrary effects on BGC-823 cells. Silencing of MALAT1 also significantly inhibited the tumor growth in mice. In addition, MALAT1 negatively regulated its target miR-22-3p. Silencing of miR-22-3p reversed the anti-tumor effects of MALAT1 silencing on GC cells. MiR-22-3p negatively regulated its target ErbB3. Silencing of ErbB3 reversed the tumor-promoting effects of miR-22-3p silencing on GC cells.ConclusionSilencing of MALAT1 inhibited the proliferation and promoted the apoptosis of GC cells through upregulating miR-22-3p and downregulating ErbB3.

LncRNA MALAT1 prevents the protective effects of miR-125b-5p against acute myocardial infarction through positive regulation of NLRC5.

Acute myocardial infarction (AMI), as the first manifestation of ischemic heart disease, is the most common cause of death in developed countries. A recent study showed that metastasis associated lung adenocarcinoma transcript 1 (MALAT1), a prognostic marker for lung cancer metastasis, could promote myocardial ischemia-reperfusion injury by regulating the levels of microRNA (miR)-145. In order to elucidate the biological function of MALAT1 in the pathogenesis of AMI and to explore the mechanisms underlying its action, an AMI rat model was established by ligation of the left anterior descending coronary artery. Downregulation of MALAT1 by siRNA transfection attenuated heart damage in an AMI model rat. The mouse cardiomyocyte cell line HL-1 was used to show that downregulation of nucleotide binding and oligomerization domain-like receptor C5 (NLRC5) and upregulation of miR-125b-5p were the results of MALAT1 silencing. TargetScan and a dual-luciferase reporter assay indicated that NLRC5 is a direct target of miR-125b-5p. Overexpression of miR-125b-5p significantly reduced hypoxia/reperfusion-induced apoptosis of HL-1 cells, an effect that could be blocked by NLCR5 overexpression. Taken together, these results suggest that MALAT1 reduced the protective effect of miR-125b-5p on injured cells through upregulation of NLCR5. This study highlights the role of MALAT1 in the pathogenesis of AMI and may guide future genetic therapeutic strategies for AMI treatment.

MiR‐124‐3p availability is antagonized by LncRNA‐MALAT1 for Slug‐induced tumor metastasis in hepatocellular carcinoma

BackgroundAs an oncogene, long noncoding RNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) can promote tumor metastasis. Hyperexpression of MALAT1 has been observed in many malignant tumors, including hepatocellular carcinoma (HCC). However, the role and mechanism of MALAT1 in HCC remain unclear.MethodsThirty human HCC and paracancerous tissue specimens were collected, and the human hepatoma cell lines Huh7 and HepG2 were cultured according to standard methods. MALAT1 and Snail family zinc finger (Slug) expression were measured by real‐time PCR, immunohistochemistry, and western blotting. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay verified the direct interaction between miR‐124‐3p and Slug(SNAI2) or MALAT1. Wound healing and transwell assays were performed to examine invasion and migration, and a subcutaneous tumor model was established to measure tumor progression in vivo.ResultsMALAT1 expression was upregulated in HCC tissues and positively correlated with Slug expression. MALAT1 and miR‐124‐3p bind directly and reversibly to each other. MALAT1 silencing inhibited cell migration and invasion. miR‐124‐3p inhibited HCC metastasis by targeting Slug.ConclusionsMALAT1 regulates Slug through miR‐124‐3p, affecting HCC cell metastasis. Thus, the MALAT1/miR‐124‐3p/Slug axis plays an important role in HCC.

LncRNA MALAT1 mediates proliferation of LPS treated-articular chondrocytes by targeting the miR-146a-PI3K/Akt/mTOR axis

The study aimed to investigate the regulation of long noncoding RNA (lncRNA), Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in osteoarthritis (OA) development. Isolated rat chondrocytes treated with lipopolysaccharide (LPS) were used as OA cell model. Results from quantitative real-time PCR (Q-PCR) showed that, in OA patients and OA cell model, the expression of MALAT1 and PI3K was clearly reduced, while the miR-146a levels were increased. Next, MALAT1 was silenced in LPS-treated chondrocytes. Following with MALAT1 silencing, the generation of Cyclooxygenase-2 (COX-2), Interleukin-6 (IL-6) and Matrix metallopeptidase-13 (MMP-13) were promoted, while the level of type II collagen (COL2) was inhibited. Moreover, MALAT1 silencing caused a significant reduction in the proliferative rate of LPS-treated chondrocytes through inducing apoptosis. Bioinformatics prediction and dual-luciferase reporter assay (DLRA) results showed that MALAT1 targets miR-146a. MALAT1 silencing also resulted in the upregulation of miR-146a. Further studies revealed that miR-146a has the opposite effect on MALAT1, and its inhibition can antagonize the function of MALAT1 silencing on cell proliferation and apoptosis. Additionally, the 3′-UTR of the Phosphoinositide 3-kinase (PI3K) gene was found to be a target of miR-146a, while PI3K protein and mRNA expression, as well as the activation of downstream Akt and mammalian target of rapamycin (mTOR) were clearly reduced upon transfection with a miR-146a mimic. These results show that MALAT1 can modulate ECM catabolism, inflammation, and especially apoptosis in chondrocytes treated with LPS, which targets PI3K/Akt/mTOR to eventually regulate the progression of OA. Our findings provide a novel regulatory mechanism of MALAT1 in OA.

Exercise Reduces Insulin Resistance in Type 2 Diabetes Mellitus via Mediating the lncRNA MALAT1/MicroRNA-382-3p/Resistin Axis

Insulin resistance (IR) is the primary pathological mechanism underlying type 2 diabetes mellitus (T2DM). Here, the study aimed to ascertain whether and how exercise mediates IR in T2DM. An in vivo mouse model of high-fat diet-induced IR and an in vitro high-glucose-induced IR model were constructed. High long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression was detected in T2MD and was positively correlated with HOMA-IR and resistin levels. Then, short hairpin RNA targeting MALAT1 (sh-MALAT1) or pcDNA-MALAT1 was delivered into human umbilical vein endothelial cells (HUVECs) to knock down or upregulate its expression, respectively. Silencing of MALAT1 resulted in reduced levels of resistin, Ang II, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), endothelin-1 (ET-1), and p-insulin receptor substrate-1 (p-IRS)/ISR-1, and decreased cell migration, as well as enhanced glucose uptake and levels of nitric oxide (NO) and p-Akt/Akt. In the IR mouse model, exercise was observed to downregulate MALAT1 to reduce resistin, whereby exercise reduced homeostatic model assessment-insulin resistance (HOMA-IR). Besides, exercise also elevated microRNA-382-3p (miR-382-3p) expression in the serum of IR mice. Dual-luciferase reporter and RNA binding protein immunoprecipitation (RIP) assays identified that MALAT1 could bind to miR-382-3p to upregulate resistin. Collectively, the key observations of the study provide evidence that inhibition of MALAT1 elevates miR-382-3p to repress resistin, which consequently underlies the mechanism of exercise protecting against IR, highlighting a direction for T2DM therapy development.

Reciprocal interplay of miR-497 and MALAT1 promotes tumourigenesis of adrenocortical cancer.

Adrenocortical carcinoma (ACC) has high recurrence rates and poor prognosis with limited response to conventional cancer therapy. Recent contributions of high-throughput transcriptomic profiling identified microRNA-497 (miR-497) as significantly underexpressed, while lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) as overexpressed in ACC. miR-497 is located in the chromosomal region 17p13.1, in which there is a high frequency of loss of heterozygosity in ACC. We aim to investigate the interaction of miR-497 and MALAT1 in ACC and its functional roles in the process of tumourigenesis. In this study, we demonstrated miR-497 post-transcriptionally repressed MALAT1 while MALAT1 also competes for miR-497 binding to its molecular target, EIF4E (eukaryotic translation initiation factor 4E). We showed that overexpression of miR-497 and silencing of MALAT1 suppressed cellular proliferation and induced cell cycle arrest through downregulation of EIF4E expression. Furthermore, MALAT1 directly binds to SFPQ (splicing factor proline and glutamine rich) protein, indicating its multifaceted roles in ACC pathophysiology. This is the first study to identify the feedback axis of miR-497-MALAT1/EIF4E in ACC tumourigenesis, providing novel insights into the molecular functions of noncoding RNAs in ACC.

MALAT1-Driven Inhibition of Wnt Signal Impedes Proliferation and Inflammation in Fibroblast-Like Synoviocytes Through CTNNB1 Promoter Methylation in Rheumatoid Arthritis.

Fibroblast-like synoviocytes (FLSs) participate in the pathogenesis of rheumatoid arthritis (RA). Emerging evidence has highlighted the role of long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and its potential involvement in RA. In this study, we test the hypothesis that the MALAT1 might inhibit proliferation and inflammatory response of FLSs in RA. The expression of MALAT1 was examined in synovial tissues from patients with RA. The effect of MALAT1 on cultured FLSs was analyzed by introducing overexpressed MALAT1 or short hairpin RNA (shRNA) against MALAT1. To validate whether methylation of CTNNB1 promoter was affected by MALAT1 alternation, we assessed the recruitment of DNA methyltransferases to CTNNB1 promoter. In cultured FLSs with shRNA-mediated CTNNB1 knockdown or activated Wnt signaling, we found the interaction between CTNNB1 and Wnt signaling. MALAT1 expression was reduced in synovial tissues of RA. MALAT1 could bind to CTNNB1 promoter region and recruit methyltransferase to promote CTNNB1 promoter methylation, thereby inhibiting CTNNB1. Notably, MALAT1 could suppress the transcription and expression of CTNNB1, thereby modulating the Wnt signaling pathway. Silenced MALAT1 stimulated the nucleation of β-catenin and the secretion of inflammatory cytokines including interleukin-6, interleukin-10, and tumor necrosis factor-α. Additionally, shRNA-mediated MALAT1 silencing elevated proliferation and suppressed apoptosis of FLSs accompanied. These findings provide evidence for the inhibitory effect of MALAT1 on proliferation and inflammation of FLSs by promoting CTNNB1 promoter methylation and inhibiting the Wnt signaling pathway. Therefore, this study provides a candidate therapeutic target for RA.

Long non‑coding RNA MALAT1 sponges miR‑124‑3p.1/KLF5 to promote pulmonary vascular remodeling and cell cycle progression of pulmonary artery hypertension.

Previous studies have demonstrated that long non-coding RNA (lncRNA) is involved in vascular remodeling. The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) lncRNA is associated with the proliferation and migration of vascular smooth muscle and endothelial cells; however, its biological role in pulmonary artery hypertension (PAH) is currently unclear. The aim of the present study was to investigate the post-transcriptional regulation of MALAT1 in human pulmonary artery smooth muscle cells (HPASMCs). The results revealed that MALAT1 expression levels were significantly upregulated in the pulmonary arteries (PAs) and HPASMCs obtained from patients with PAH compared with adjacent normal PA tissues and HPASMCs. Knockdown of MALAT1 suppressed the viability and proliferation of HPASMCs and prevented cells entering the G0/G1 cell cycle phase. MALAT1 overexpression exerted the opposite effects. Bioinformatics analysis predicted complementary binding of hsa-microRNA (miR)-124-3p.1 with the 3′-untranslated region of MALAT1. Luciferase reporter assays and RNA immunoprecipitation experiments demonstrated molecular binding between MALAT1 and hsa-miR-124-3p.1. This resulted in the formation of an RNA-induced silencing complex. In addition, Kruppel-like factor 5 (KLF5) was confirmed to be a target gene of MALAT1/hsa-miR-124-3p.1. MALAT1 silencing did not inhibit the proliferation and migration of HPASMCs following knockdown of hsa-miR-124-3p.1. In addition, MALAT1 knockdown was demonstrated to attenuate the expression of KLF5. Following MALAT1 knockdown, the expression level of KLF5 was rescued by inhibition of hsa-miR-124-3p.1 expression. The results of the current study indicate that the MALAT1/hsa-miR-124-3p.1/KLF5 axis may serve a key role in HPASMCs. In addition, the results contribute to what is known regarding the role of MALAT1 in PAH development and provide a novel theoretical basis for the development of new therapeutic interventions for patients with PAH.

Silencing of lncRNA MALAT1 Prevents Inflammatory Injury after Lung Transplant Ischemia-Reperfusion by Downregulation of IL-8 via p300

Ischemia-reperfusion injury is a common early complication after lung transplantation. It was reported that long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in ischemia-reperfusion injury and regulates inflammation. This study aimed to explore the role of MALAT1 in inflammatory injury following lung transplant ischemia-reperfusion (LTIR). A LTIR rat model was successfully established, with the expression of MALAT1 and interleukin-8 (IL-8) in lung tissues detected. Then, in vitro loss- and gain-of-function investigations were conducted to evaluate the effect of MALAT1 on pulmonary epithelial cell apoptosis and IL-8 expression. The relationship among MALAT1, p300, and IL-8 was tested. Moreover, a sh-MALAT1-mediated model of LTIR was established in vivo to examine inflammatory injury and chemotaxis infiltration. Both IL-8 and MALAT1 were highly expressed in LTIR. MALAT1 interacted with p300 to regulate the IL-8 expression by recruiting p300. Importantly, silencing of MALAT1 inhibited the chemotaxis of neutrophils by downregulating IL-8 expression via binding to p300. Besides, MALAT1 silencing alleviated the inflammatory injury after LTIR by downregulating IL-8 and inhibiting infiltration and activation of neutrophils. Collectively, these results demonstrated that silencing of MALAT1 ameliorated the inflammatory injury after LTIR by inhibiting chemotaxis of neutrophils through p300-mediated downregulation of IL-8, providing clinical insight for LTIR injury.

Inhibition of MALAT1 reduces tumor growth and metastasis and promotes drug sensitivity in colorectal cancer

Human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA known to be highly expressed in several tumors. In colorectal cancer (CRC), MALAT1 promotes cell proliferation, metastasis, and invasion in vitro and in vivo. This study aimed to investigate the effect of MALAT1 on the proliferation, migration, and drug sensitivity of CRC cells in vitro and in vivo and the mechanisms involved therein. We observed increased expression of MALAT1 in six CRC cell lines compared to that in normal cells, suggesting its involvement in CRC progression. Downregulation of MALAT1 inhibited cell migration and induced apoptosis in vitro and inhibited tumor growth and metastasis in nude mice. Furthermore, MALAT1 silencing downregulated the expression of ATP-binding cassette transporters (ABC), breast cancer resistance protein (BCRP), and multi-drug resistance proteins including MDR1 and MRP1, resulting in decreased resistance of cancer cells to 5-FU. In addition, the metastasis and invasion of HCT-116 and HCT-116/5-FU cells were regulated via targeting miR-20b-5p. Based on these observations, we infer that inhibition of MALAT1 suppressed CRC progression and metastasis and improved the sensitivity of cancer cells to 5-FU. The present study proposes a new direction to investigate the molecular mechanisms underlying the invasion and metastasis of CRC, whereby the interaction between MALAT1 and miR-20b-5p could be a novel therapeutic target for CRC.

Silencing of lncRNA MALAT1 inhibits cell cycle progression via androgen receptor signaling in prostate cancer cells

Prostate cancer is the second common cancer in men with high morbidity and mortality. Androgen receptor (AR) signaling plays a crucial role in occurrence and development of prostate cancer. In this study, we demonstrated that lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was increased in prostate cancer cells after androgen stimulation, as well as AR. The silencing of MALAT1 inhibited dihydrotestosterone (DHT) administration-induced acceleration of proliferation and cell cycle progression, and increase of AR expression in prostate cancer cells. MALAT1 bound to miR-320b and negatively regulated its expression, and vice versa. AR is a target of miR-320b. The phenotypic changes induced by silencing of MALAT1 were abolished by miR-320b inhibition or AR overexpression. Additionally, MALAT1 knockdown also suppressed the tumorigenesis of prostate cancer cells in nude mice. In summary, the silencing of MALAT1 inactivated AR signaling by sponging miR-320b, and inhibited proliferation and cell cycle progression in prostate cancer cells, suggesting that MALAT1 may be a new target in diagnosis and therapy of prostate cancer in clinic.

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.

LncRNA MALAT1/MiR-145 Adjusts IL-1β-Induced Chondrocytes Viability and Cartilage Matrix Degradation by Regulating ADAMTS5 in Human Osteoarthritis.

PurposeAccumulating evidence suggests that microRNA-145 (miR-145) plays an important role in osteoarthritis (OA), which is a chronic progressive joint disease. Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes metastasis in cancers and functions as a sponge for miR-145. However, the role of MALAT1/miR-145 in OA pathogenesis has not yet been elucidated.Materials and MethodsThe expression of MALAT1 and miR-145 was examined by quantitative real-time PCR; the interaction between miR-145, MALAT1 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 5 was verified by luciferase reporter assay. Correlations among MALAT1, miR-145, and ADAMTS5 were analyzed by Spearman rank analysis. Chondrocytes viability and cartilage extracellular matrix (ECM) degradation were investigated with cell viability assay and Western blotting analyzing expression of ADAMTS5, collagen type 2 alpha 1 (COL2A1), aggrecan (ACAN), and cartilage oligomeric matrix protein (COMP).ResultsMALAT1 was upregulated, and miR-145 was downregulated in OA samples and IL-1β-induced chondrocytes. Mechanically, miR-145 could directly bind to MALAT1 and ADAMTS5. Moreover, miR-145 expression was negatively correlated with MALAT1 and ADAMTS5 expression in OA patients, whereas MALAT1 and ADAMTS5 expression was positively correlated. Functionally, overexpression of MALAT1 inhibited chondrocyte viability and promoted cartilage ECM degradation in IL-1β-induced chondrocytes. In support thereof, MALAT1 silencing and miR-145 upregulation exerted the opposite effect in IL-1β-induced chondrocytes. Moreover, the effect of MALAT1 was counteracted by miR-145 upregulation, and ADAMTS5 restoration could abate miR-145 effects.ConclusionAn MALAT1/miR-145 axis contributes to ECM degradation in IL-1β-induced chondrocytes through targeting ADAMTS5, suggesting that MALAT1/miR-145/ADAMTS5 signaling may underlie human OA pathogenesis.

LncRNA MALAT1 promotes oxidized low-density lipoprotein-induced autophagy in HUVECs by inhibiting the PI3K/AKT pathway.

Emerging evidence suggests that long noncoding RNAs (lncRNAs) are involved in many biological processes, such as cell growth, differentiation, apoptosis, and autophagy. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), highly expressed in endothelial cells, is well conserved and implicated in endothelial cell migration and proliferation. However, whether MALAT1 participates in oxidized low-density lipoprotein (ox-LDL)-induced autophagy regulation in human umbilical vein endothelial cells (HUVECs) remains unknown. In this study, we observed that autophagy was upregulated and MALAT1 expression was markedly increased in HUVECs treated with ox-LDL. The ox-LDL-induced autophagy of HUVECs is significantly associated with the PI3K/AKT pathway. Furthermore, we found that MALAT1 overexpression inhibited PI3K, Akt and p70S6K phosphorylation and downregulated RHEB expression, simultaneously increasing ox-LDL-induced autophagy. MALAT1 silencing caused higher phosphorylated PI3K, Akt and p70S6K levels, upregulated RHEB expression and markedly suppressed autophagy. These results indicated that lncRNA MALAT1 promotes ox-LDL-induced autophagy in HUVECs partly through the PI3K/AKT signaling pathway.

LncRNA MALAT1 promotes cell proliferation and imatinib resistance by sponging miR-328 in chronic myelogenous leukemia

BackgroundChronic myeloid leukemia (CML) is a type of cancer that starts in certain blood-forming cells of the bone marrow. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a well known protooncogene, has be shown to be upregulated in various tumor types, including multiple myeloma. However, the biological function of MALAT1 in CML remains has yet to be explored. This study was designed to investigate the effects of MALAT1 on the physiological processes in CML and its underlying mechanisms, which will be helpful for us to have a better understanding of CML development and progression as well as improved therapeutic method. MethodsRecombinant virus construction and infection was performed to overexpress or knockdown the expression of MALAT1. Dual luciferase reporter assay was applied to vetify the interaction between MALAT1 and miR-328. The cell viability and cell cycle were analyzed by CCK-8 assay and flow cytometry, respectively. Quantitative real time PCR and western blotting assays were used to measure the expression of genes and proteins. ResultsThe expression of MALAT1 was significantly increased in CML cells compared with peripheral blood cells from health donors. Silencing of MALAT1 significantly inhibited the proliferation and arrested cell cycle of CML cells by targeting miR-328. Moreover, MALAT1 knockdown enhanced imatinib sensitivity of K562 cells, while silencing of miR-328 abolished this effect. ConclusionsThese findings indicate that lncRNA MALAT1/miR-328 axis promotes the proliferation and imatinib resistance of CML cells, providing new perspectives for the future study of MALAT1 as a therapeutic target for CML.