MALAT1

Gene Summary

Gene:MALAT1; metastasis associated lung adenocarcinoma transcript 1 (non-protein coding)
Aliases: HCN, NEAT2, PRO2853, LINC00047, NCRNA00047
Location:11q13.1
Summary:This gene produces a precursor transcript from which a long non-coding RNA is derived by RNase P cleavage of a tRNA-like small ncRNA (known as mascRNA) from its 3' end. The resultant mature transcript lacks a canonical poly(A) tail but is instead stabilized by a 3' triple helical structure. This transcript is retained in the nucleus where it is thought to form molecular scaffolds for ribonucleoprotein complexes. It may act as a transcriptional regulator for numerous genes, including some genes involved in cancer metastasis and cell migration, and it is involved in cell cycle regulation. Its upregulation in multiple cancerous tissues has been associated with the proliferation and metastasis of tumor cells. [provided by RefSeq, Mar 2015]
Databases:OMIM, HGNC, GeneCard, Gene
Source:NCBIAccessed: 09 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 09 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MALAT1 (cancer-related)

Zhang Y, Chen Z, Li MJ, et al.
Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 regulates the expression of Gli2 by miR-202 to strengthen gastric cancer progression.
Biomed Pharmacother. 2017; 85:264-271 [PubMed] Related Publications
BACKGROUND: Gastric cancer (GC) is one of the most common malignancies and ranks the second leading cause of cancer death worldwide. Some studies had reported the tumor-promoting effects of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) as a competing endogenous RNA (ceRNA) by sponging to microRNAs. However, the molecular mechanism of ceRNA regulatory pathway involving MALAT1 in GC remains unclear.
METHODS: MALAT1 and miR -202 expression was detected by quantitative real time PCR (qRT-PCR) in 60 gastric cancer tissues and adjacent normal tissues, CCK8 cell proliferation assays, cell cycle analysis and cell apoptosis assays were performed to detect the GC cell proliferation and apoptosis. The mRNA and protein levels of Gli2 were analyzed by quantitative real-time PCR and Western blotting assays. Furthermore, using online software, luciferase reporter assays, RNA immunoprecipitation (RIP) and RNA pulldown assays demonstrated miR-202 was a target of MALAT1.
RESULTS: We found that MALAT1 was upregulated in GC tissues and higher MALAT1 expression was correlated with larger tumor size, lymph node metastasis, and TNM stage. Moreover, we revealed that MALAT1 was a direct target of miR-202 and knockdown of MALAT1 significantly decreased the expression of Gli2 through negatively regulating miR-202. In addition, knockdown of Malat1 inhibited GC cells proliferation, S-phase cell number, and induced cell apoptosis via negatively regulating miR-202 in vitro.
CONCLUSIONS: Our results elucidated MALAT1/miR-202/Gli2 regulatory pathway, which maybe contribute to a novel therapeutic strategy for GC patients.

Huang C, Yu Z, Yang H, Lin Y
Increased MALAT1 expression predicts poor prognosis in esophageal cancer patients.
Biomed Pharmacother. 2016; 83:8-13 [PubMed] Related Publications
AIM: This study was designed to determine the expression of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in patients with esophageal cancer (EC). In addition, we attempted to seek the prognostic value of MALAT1 in EC based on its expression.
METHODS: The expression of MALAT1 in EC tissues and cell lines were measured by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). The association between MALAT1 expression and the clinical characteristics was analyzed using Chi-square test. Kaplan-Meier survival curves were plotted to describe the overall survival of EC patients with different expression of MALAT1. Cox regression analysis was per formed to evaluate the prognostic value of MALAT1 for EC patients.
RESULTS: Expression levels of MALAT1 were significantly higher in EC tissues and cells than the controls (P<0.05). MALAT1 expression was tightly related to lymphatic invasion (P=0.018), distant metastasis (P=0.033) and tumor differentiation (P=0.025), but shared no association with age, gender and tumor location (P>0.05). In addition, patients with high MALAT1 expression had a shorter overall survival than those with low MALAT1 (P<0.001). The results of Cox analysis shown that MALAT1 was significantly linked with the prognosis of EC patients (HR=6.638; P=0.000; 95% CI=2.948-14.947).
CONCLUSION: Taken together, the expression of MALAT1 could be a predictor for prognosis of EC patients.

Huang JK, Ma L, Song WH, et al.
MALAT1 promotes the proliferation and invasion of thyroid cancer cells via regulating the expression of IQGAP1.
Biomed Pharmacother. 2016; 83:1-7 [PubMed] Related Publications
BACKGROUND: Increasing evidence indicated that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acted as a key regulator in the proliferation and invasion of several cancers. However, the function of MALAT1 in the development of thyroid cancer has not been experimentally established.
METHODS: The expression of MALAT1 and IQGAP1 in thyroid cancer tissues and cells were detected by quantitative real-time PCR and western blot. The effects of MALAT1 and IQGAP1 on the cell proliferation and invasion of thyroid cancer cells were detected with a 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium 4 (MTT) assay and a Transwell assay, respectively. FTC-133 or SW1736 transfected with si-MALAT1 or pcDNA-MALAT1 were injected subcutaneously into 4-week-olds BALB/c mice to examine the impact of MALAT1 on the tumor development of thyroid cancer in vivo.
RESULTS: In this study, we discovered the higher level of MALAT-1 and expression of IQGAP1 in thyroid cancer tissues and in thyroid cancer cells compared to that in the control. MTT and Transwell assay showed that the proliferation and invasion of FTC-133 cells with MALAT-1 knockdown were inhibited. Moreover, MALAT-1 could upregulate the expression of IQGAP1 in thyroid cancer cells. In addition, IQGAP1 knockdown reversed the decreasing cell proliferation and invasion of thyroid cancer induced by MALAT-1 overexpression. Finally, the study in vivo verified that MALAT-1 promoted the tumor growth of thyroid cancer.
CONCLUSION: Our study indicated that MALAT1 promoted the proliferation and invasion of thyroid cancer cells via regulating the expression of IQGAP1.

Zhang R, Hardin H, Huang W, et al.
MALAT1 Long Non-coding RNA Expression in Thyroid Tissues: Analysis by In Situ Hybridization and Real-Time PCR.
Endocr Pathol. 2017; 28(1):7-12 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Long non-coding RNAs (lncRNAs) are important for transcription and for epigenetic or posttranscriptional regulation of gene expression and may contribute to carcinogenesis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an lncRNA involved in the regulation of the cell cycle, cell proliferation, and cell migration, is known to be deregulated in multiple cancers. Here, we analyzed the expression of MALAT1 on 195 cases of benign and malignant thyroid neoplasms by using tissue microarrays for RNA in situ hybridization (ISH) and real-time PCR. MALAT1 is highly expressed in normal thyroid (NT) tissues and thyroid tumors, with increased expression during progression from NT to papillary thyroid carcinomas (PTCs) but is downregulated in poorly differentiated thyroid cancers (PDCs) and anaplastic thyroid carcinomas (ATCs) compared to NT. Induction of epithelial to mesenchymal transition (EMT) by transforming growth factor (TGF)-beta in a PTC cell line (TPC1) led to increased MALAT1 expression, supporting a role for MALAT1 in EMT in thyroid tumors. This is the first ISH study of MALAT1 expression in thyroid tissues. It also provides the first piece of evidence suggesting MALAT1 downregulation in certain thyroid malignancies. Our findings support the notion that ATCs may be molecularly distinct from low-grade thyroid malignancies and suggest that MALAT1 may function both as an oncogene and as a tumor suppressor in different types of thyroid tumors.

Miao Y, Fan R, Chen L, Qian H
Clinical Significance of Long Non-coding RNA MALAT1 Expression in Tissue and Serum of Breast Cancer.
Ann Clin Lab Sci. 2016; 46(4):418-24 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) have been proven to serve a critical role in cancer development and progression. The aim of this study was to elucidate clinical significance of lncRNA MALAT1 expression in breast cancer (BC). A total of 78 BC patients treated with radical resection were enrolled in this study. Quantitative reverse transcription-polymerase chain reaction was used to detect MALAT1 expression in tissues and serum samples. The receiver operating characteristics (ROC) curve was constructed to describe diagnostic specificity and sensitivity. Lentivirus-mediated RNA interference was used to knockdown MALAT1 in the MDA-MB-231 cell line, and then cell proliferation and invasion were explored. Results showed that MALAT1 expression was significantly up-regulated in 85.9% (67/78) of cancerous tissues compared with normal counterparts (P<0.01). Further, an elevated MALAT1 expression in BC tissue was significantly associated with lymph metastasis (P=0.037) and adverse 5-year disease-free survival (mean 48.5 months vs 62.7 months, P=0.012). Suppression of lncRNA MALAT1 significantly inhibited BC cells proliferation, migration and invasion, induced apoptosis and cell cycle G1 arrest. In addition, serum MALAT1 levels in BC patients were much higher than levels in patients with benign breast disease (P<0.001), its diagnostic efficacy was satisfactory, area under the curve (AUC) was 0.833. In conclusion, MALAT1 upregulation plays an important rolein BC development, and serum MALAT1 level may be a potential tumor marker for BC diagnosis.

Soudyab M, Iranpour M, Ghafouri-Fard S
The Role of Long Non-Coding RNAs in Breast Cancer.
Arch Iran Med. 2016; 19(7):508-17 [PubMed] Related Publications
Long non-coding RNA (lncRNA) genes are an important population of non-coding RNAs with defined key roles in normal development as well as tumorigenesis process. Evidences suggest that they can be classified as tumor suppressor genes or oncogenes according to their functions and expression pattern in tumoral tissues. They have been shown to regulate the plasticity of cancer stem cells. Their important roles in the regulation of cancer-related pathways in addition to deregulation of their expression in a number of cancers have suggested that they can be used as markers for cancer detection and prognosis, as well as targets for cancer treatment. Deregulation of a number of lncRNAs, such as HOTAIR, XIST, MALAT, and H19 has been detected in breast cancer samples and cell lines. In addition, the association between lncRNAs signature and breast cancer patients' survival has been assessed in various studies. Here, the expression patterns of lncRNAs in breast cancer, as well as their significance in prognosis and patient treatment are discussed.

Xiang J, Guo S, Jiang S, et al.
Silencing of Long Non-Coding RNA MALAT1 Promotes Apoptosis of Glioma Cells.
J Korean Med Sci. 2016; 31(5):688-94 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
The metastasis-associated lung adenocarcinoma transcription 1 (MALAT1) is a highly conserved long non-coding RNA (lncRNA) gene. However, little is known about the pathological role of lncRNA MALAT1 in glioma. In the present study, we explored the expression level of lncRNA MALAT1 in primary glioma tissues as well as in U87 and U251 glioma cell lines. Using qRT-PCR, we found that the expression of lncRNA MALAT1 was significantly increased in glioma tissues compared with that of paracancerous tissues. Meanwhile, the expression of MALAT1 was highly expressed in U98 and U251 cells. In order to explore the function of MALAT1, the expression of MALAT1 was greatly reduced in U87 and U251 cells transfected with siRNA specifically targeting MALAT1. Consequently, cell viability of U87 and U251 cells were drastically decreased after the knockdown of MALAT1. Concomitantly, the apoptosis rate of the two cell lines was dramatically increased. Furthermore, the expression levels of some tumor markers were reduced after the knockdown of MALAT1, such as CCND1 and MYC. In summary, the current study indicated a promoting role of MALAT1 in the development of glioma cell.

Gilroy KL, Terry A, Naseer A, et al.
Gamma-Retrovirus Integration Marks Cell Type-Specific Cancer Genes: A Novel Profiling Tool in Cancer Genomics.
PLoS One. 2016; 11(4):e0154070 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Retroviruses have been foundational in cancer research since early studies identified proto-oncogenes as targets for insertional mutagenesis. Integration of murine gamma-retroviruses into the host genome favours promoters and enhancers and entails interaction of viral integrase with host BET/bromodomain factors. We report that this integration pattern is conserved in feline leukaemia virus (FeLV), a gamma-retrovirus that infects many human cell types. Analysis of FeLV insertion sites in the MCF-7 mammary carcinoma cell line revealed strong bias towards active chromatin marks with no evidence of significant post-integration growth selection. The most prominent FeLV integration targets had little overlap with the most abundantly expressed transcripts, but were strongly enriched for annotated cancer genes. A meta-analysis based on several gamma-retrovirus integration profiling (GRIP) studies in human cells (CD34+, K562, HepG2) revealed a similar cancer gene bias but also remarkable cell-type specificity, with prominent exceptions including a universal integration hotspot at the long non-coding RNA MALAT1. Comparison of GRIP targets with databases of super-enhancers from the same cell lines showed that these have only limited overlap and that GRIP provides unique insights into the upstream drivers of cell growth. These observations elucidate the oncogenic potency of the gamma-retroviruses and support the wider application of GRIP to identify the genes and growth regulatory circuits that drive distinct cancer types.

Wang J, Pan Y, Wu J, et al.
The Association between Abnormal Long Noncoding RNA MALAT-1 Expression and Cancer Lymph Node Metastasis: A Meta-Analysis.
Biomed Res Int. 2016; 2016:1823482 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Previous studies have investigated that the expression levels of MALAT-1 were higher in cancerous tissues than matched histologically normal tissues. And, to some extent, overexpression of MALAT-1 was inclined to lymph node metastasis. This meta-analysis collected all relevant articles and explored the association between MALAT-1 expression levels and lymph node metastasis. We searched PubMed, EmBase, Web of Science, Cochrane Library, and OVID to address the level of MALAT-1 expression in cancer cases and noncancerous controls (accessed February 2015). And 8 studies comprising 696 multiple cancer patients were included to assess this association. The odds ratio (OR) and its corresponding 95% confidence interval (CI) were calculated to assess the strength of the association using Stata 12.0 version software. The results revealed there was a significant difference in the incidence of lymph node metastasis between high MALAT-1 expression group and low MALAT-1 expression group (OR = 1.94, 95% CI 1.15-3.28, P = 0.013 random-effects model). Subgroup analysis indicated that MALAT-1 high expression had an unfavorable impact on lymph node metastasis in Chinese patients (OR = 1.87, 95% CI 1.01-2.46). This study demonstrated that the incidence of lymph node metastasis in patients detected with high MALAT-1 expression was higher than that in patients with low MALAT-1 expression in China.

Han Y, Wu Z, Wu T, et al.
Tumor-suppressive function of long noncoding RNA MALAT1 in glioma cells by downregulation of MMP2 and inactivation of ERK/MAPK signaling.
Cell Death Dis. 2016; 7:e2123 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a type of long noncoding RNA. It is associated with metastasis and is a favorable prognostic factor for lung cancer. Recent studies have shown that MALAT1 plays an important role in other malignancies. But, little is known about the role of MALAT1 in glioma. In this study, quantitative reverse transcription PCR (qRT-PCR) was used to demonstrate that the expression of MALAT1 was lower than that in normal brain tissues. Stable RNA interference-mediated knockdown of MALAT1 in human glioma cell lines (U87 and U251) significantly promoted the invasion and proliferation of the glioma cells by in vitro assays. Conversely, overexpression of MALAT1 caused significant reduction in cell proliferation and invasion in vitro, and tumorigenicity in both subcutaneous and intracranial human glioma xenograft models. Furthermore, MALAT1-mediated tumor suppression in glioma cells may be via reduction of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling activity and expression of matrix metalloproteinase 2 (MMP2). In conclusion, overall data demonstrated the tumor-suppressive role of MALAT1 in glioma by attenuating ERK/MAPK-mediated growth and MMP2-mediated invasiveness.

Chou J, Wang B, Zheng T, et al.
MALAT1 induced migration and invasion of human breast cancer cells by competitively binding miR-1 with cdc42.
Biochem Biophys Res Commun. 2016; 472(1):262-9 [PubMed] Related Publications
Competitive endogenous messenger RNAs (ceRNAs) affect other RNAs transcription through competitively binding common microRNAs (miRNAs). In this study we identified long non-coding RNA (lncRNA) MALAT1 can function as a ceRNA of cell division cycle 42 (cdc42) 3'UTR in inducing migration and invasion of breast cancer cells via miR-1. We found that miR-1 bound both MALAT1 and cdc42 3'UTR directly. Further study showed that MALAT1 induced migration and invasion of breast cancer cells while reduced the level of cdc42. Our results suggest that MALAT1 regulated migration and invasion of breast cancer cells via affecting cdc42 through binding miR-1 competitively.

Bamodu OA, Huang WC, Lee WH, et al.
Aberrant KDM5B expression promotes aggressive breast cancer through MALAT1 overexpression and downregulation of hsa-miR-448.
BMC Cancer. 2016; 16:160 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
BACKGROUND: Triple negative breast cancers (TNBC) possess cell dedifferentiation characteristics, carry out activities connate to those of cancer stem cells (CSCs) and are associated with increased metastasis, as well as, poor clinical prognosis. The regulatory mechanism of this highly malignant phenotype is still poorly characterized. Accruing evidence support the role of non-coding RNAs (ncRNAs) as potent regulators of CSC and metastatic gene expression, with their dysregulation implicated in tumorigenesis and disease progression.
METHODS: In this study, we investigated TNBC metastasis, metastasis-associated genes and potential inhibitory mechanisms using bioinformatics, tissue microarray analyses, immunoblotting, polymerase chain reaction, loss and gain of gene function assays and comparative analyses of data obtained.
RESULTS: Compared with other breast cancer types, the highly metastatic MDA-MB-231 cells concurrently exhibited increased expression levels of Lysine-specific demethylase 5B protein (KDM5B) and long non-coding RNA (lncRNA), MALAT1, suggesting their functional association. KDM5B-silencing in the TNBC cells correlated with the upregulation of hsa-miR-448 and led to suppression of MALAT1 expression with decreased migration, invasion and clonogenic capacity in vitro, as well as, poor survival in vivo. This projects MALAT1 as a mediator of KDM5B oncogenic potential and highlights the critical role of this microRNA, lncRNA and histone demethylase in cancer cell motility and metastatic colonization. Increased expression of KDM5B correlating with disease progression and poor clinical outcome in breast cancer was reversed by hsa-miR-448.
CONCLUSIONS: Our findings demonstrate the critical role of KDM5B and its negative regulator hsa-miR-448 in TNBC metastasis and progression. Hsa-miR-448 disrupting KDM5B-MALAT1 signalling axis and associated activities in TNBC cells, projects it as a putative therapeutic factor for selective eradication of TNBC cells. Graphical abstract KDM5B, MALAT1 and hsa-miR-448 are active looped components of the epigenetic poculo mortis in aggressive breast cancer.

Wang J, Xu AM, Zhang JY, et al.
Prognostic significance of long non-coding RNA MALAT-1 in various human carcinomas: a meta-analysis.
Genet Mol Res. 2016; 15(1) [PubMed] Related Publications
The long non-coding RNA MALAT-1 plays an important role in cancer prognosis. The present research aimed to elucidate its precise predictive value in various human carcinomas. A quantitative meta-analysis was performed by searching PubMed, Embase, Web of Science, and Cochrane Library (most recently, January 2015) databases, and extracting data from studies that investigated the association between MALAT-1 expression and survival outcomes in patients of various cancers. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated as a measure of generalized effect. This meta-analysis included 1317 cases from 12 datasets. Our investigation revealed that poor overall survival (OS; HR = 2.14, 95% CI = 1.74-2.64) and shortened disease-free, recurrence-free, disease-specific, or progression-free survival (HR = 2.13, 95% CI = 1.22-3.72) can be predicted by high MALAT-1 expression for various cancers. Moreover, elevated MALAT-1 levels significantly correlated with decreased OS in a renal cell carcinoma (RCC) subgroup (HR = 3.43, 95% CI = 1.80-6.53). These results imply that MALAT-1 can be used to predict unfavorable prognoses for several cancers, particularly RCC.

Guo F, Guo L, Li Y, et al.
MALAT1 is an oncogenic long non-coding RNA associated with tumor invasion in non-small cell lung cancer regulated by DNA methylation.
Int J Clin Exp Pathol. 2015; 8(12):15903-10 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
MALAT1 is an important long noncoding RNA in tumor progression. Here we showed that the expression of MALAT1 was upregulated in non-small cell lung cancer cells (NSCLCs) or tissues as compared with the normal lung cell or tissues. Thus, the knockdown of MALAT1 led to decreased cell migration and invasion. Next we also found that CXCL5 as a downstream gene of MALAT1 regulated cell migration and invasion. However the regulation of MALAT1 expression was rarely known. Here we found that the treatment with SAM suppressed of MALAT1 expression. Finally, we showed that the methylated forms of MALAT1 promoter in lung cancer cells or tissues decreased compared with normal lung cells or tissues. These demonstrated that the expression of MALAT1 was dependent on the methylation. Overall, our findings illuminate the oncogenic function of MALAT1 which is regulated by DNA methylation that might provide potential clinical application in NSCLC.

Tee AE, Liu B, Song R, et al.
The long noncoding RNA MALAT1 promotes tumor-driven angiogenesis by up-regulating pro-angiogenic gene expression.
Oncotarget. 2016; 7(8):8663-75 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Neuroblastoma is the most common solid tumor during early childhood. One of the key features of neuroblastoma is extensive tumor-driven angiogenesis due to hypoxia. However, the mechanism through which neuroblastoma cells drive angiogenesis is poorly understood. Here we show that the long noncoding RNA MALAT1 was upregulated in human neuroblastoma cell lines under hypoxic conditions. Conditioned media from neuroblastoma cells transfected with small interfering RNAs (siRNA) targeting MALAT1, compared with conditioned media from neuroblastoma cells transfected with control siRNAs, induced significantly less endothelial cell migration, invasion and vasculature formation. Microarray-based differential gene expression analysis showed that one of the genes most significantly down-regulated following MALAT1 suppression in human neuroblastoma cells under hypoxic conditions was fibroblast growth factor 2 (FGF2). RT-PCR and immunoblot analyses confirmed that MALAT1 suppression reduced FGF2 expression, and Enzyme-Linked Immunosorbent Assays revealed that transfection with MALAT1 siRNAs reduced FGF2 protein secretion from neuroblastoma cells. Importantly, addition of recombinant FGF2 protein to the cell culture media reversed the effects of MALAT1 siRNA on vasculature formation. Taken together, our data suggest that up-regulation of MALAT1 expression in human neuroblastoma cells under hypoxic conditions increases FGF2 expression and promotes vasculature formation, and therefore plays an important role in tumor-driven angiogenesis.

Sun R, Qin C, Jiang B, et al.
Down-regulation of MALAT1 inhibits cervical cancer cell invasion and metastasis by inhibition of epithelial-mesenchymal transition.
Mol Biosyst. 2016; 12(3):952-62 [PubMed] Related Publications
The metastasis-associated lung adenocarcinoma transcript 1(MALAT1), a member of the long non-coding RNA (lncRNA) family, has been reported to be highly enriched in many kinds of cancers and to be a metastasis marker and a prognostic factor. In this study, we found that MALAT1 expression levels were significantly increased in cervical cancer (CC) cells and tissues. The down-regulation of MALAT1 by shRNA in CC cells inhibited the invasion and metastasis in vitro and in vivo. Microarray analysis showed that the knockdown of MALAT1 up-regulated the epithelial markers E-cadherin and ZO-1, and down-regulated the mesenchymal markers β-catenin and Vimentin. This regulation was further confirmed by subsequent observation from RT-PCR, western blot, and immunofluorescence results. Meanwhile, the transcription factor snail, which functions to modulate epithelial-mesenchymal transition (EMT), was also down-regulated at both transcript and protein levels by MALAT1 down-regulation. In addition, we found that MALAT1 expression levels were positively related to HPV infection in cervical epithelial tissues by microarray analysis. Taken together, these results suggest that MALAT1 functions to promote cervical cancer invasion and metastasis via induction of EMT, and it may be a target for the prevention and therapy of cervical cancers.

Li T, Mo X, Fu L, et al.
Molecular mechanisms of long noncoding RNAs on gastric cancer.
Oncotarget. 2016; 7(8):8601-12 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. Aberrant expression of lncRNAs has been found associated with gastric cancer, one of the most malignant tumors. By complementary base pairing with mRNAs or forming complexes with RNA binding proteins (RBPs), some lncRNAs including GHET1, MALAT1, and TINCR may mediate mRNA stability and splicing. Other lncRNAs, such as BC032469, GAPLINC, and HOTAIR, participate in the competing endogenous RNA (ceRNA) network. Under certain circumstances, ANRIL, GACAT3, H19, MEG3, and TUSC7 exhibit their biological roles by associating with microRNAs (miRNAs). By recruiting histone-modifying complexes, ANRIL, FENDRR, H19, HOTAIR, MALAT1, and PVT1 may inhibit the transcription of target genes in cis or trans. Through these mechanisms, lncRNAs form RNA-dsDNA triplex. CCAT1, GAPLINC, GAS5, H19, MEG3, and TUSC7 play oncogenic or tumor suppressor roles by correlated with tumor suppressor P53 or onco-protein c-Myc, respectively. In conclusion, interaction with DNA, RNA and proteins is involved in lncRNAs' participation in gastric tumorigenesis and development.

Shi XS, Li J, Yang RH, et al.
Correlation of increased MALAT1 expression with pathological features and prognosis in cancer patients: a meta-analysis.
Genet Mol Res. 2015; 14(4):18808-19 [PubMed] Related Publications
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified as a potential cancer biomarker, yet the mechanism by which it influences the development of cancer remains unknown. In this study, we aimed to correlate MALAT1 expression with pathological features and prognosis in cancer patients. Several databases were searched using combinations of keywords relating to MALAT1 and cancer. After selection of relevant cohort studies according to strict criteria, a meta-analysis was conducted. Twelve studies were analyzed, involving 958 cancer patients. Elevated MALAT1 expression was associated with poor prognosis and larger tumors [prognosis: hazard ratio = 3.11, 95% confidence interval (CI) = 1.98-4.23, P = 0.000; tumor size: odds ratio (OR) = 0.40, 95%CI = 0.21-0.74, P = 0.003]. However, no connection with histological grade, T-stage, lymph node (LN) metastasis, or distant metastasis was established (all P > 0.05). A correlation between increased expression and poor prognosis was observed in the large and small sample-size subgroups (all P< 0.05), as was a relationship with large tumor size (OR = 0.30, 95%CI = 0.13-0.71, P = 0.006). Expression was correlated with T-stage and distant metastasis in the small sample-size subgroup (all P < 0.05), but no association was detected regarding histological grade, LN metastasis in either subgroup (all P > 0.05). Our findings demonstrate that elevated MALAT1 expression correlates with large tumor size, advanced tumor stage, and poor prognosis, and might therefore be utilized to evaluate clinical pathological features and prognostic out come for cancer patients.

Gong WJ, Yin JY, Li XP, et al.
Association of well-characterized lung cancer lncRNA polymorphisms with lung cancer susceptibility and platinum-based chemotherapy response.
Tumour Biol. 2016; 37(6):8349-58 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) play important roles in carcinogenesis and drug efficacy. Platinum-based chemotherapy is first-line treatment for lung cancer chemotherapy. In this study, we aimed to investigate the association of well-characterized lung cancer lncRNA genetic polymorphisms with the lung cancer susceptibility and platinum-based chemotherapy response. A total of 498 lung cancer patients and 213 healthy controls were recruited in the study. Among them, 467 patients received at least two cycles of platinum-based chemotherapy. Thirteen polymorphisms in HOXA distal transcript antisense RNA (HOTTIP), HOX transcript antisense intergenic RNA (HOTAIR), H19, CDKN2B antisense RNA 1 (ANRIL), colon cancer-associated transcript 2 (CCAT2), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and maternally expressed gene 3 (MEG3) genes were genotyped by allele-specific MALDI-TOF mass spectrometry. We found that patients with HOTTIP rs5883064 C allele or rs1859168 A allele had increased lung cancer risk (P = 0.01, P = 0.01, respectively). CCAT2 rs6983267 (P = 0.02, adenocarcinoma) and H19 rs2107425 (P = 0.02, age under 50 years) showed strong relationship with lung cancer susceptibility. CCAT2 rs6983267, H19 rs2839698, MALAT1 rs619586, and HOTAIR rs7958904 were associated with platinum-based chemotherapy response in dominant model ((P = 0.02, P = 0.04, P = 0.04, P = 0.01, respectively). ANRIL rs10120688 (P = 0.02, adenocarcinoma) and rs1333049 (P = 0.04, small-cell lung cancer), H19 rs2107425 (P = 0.02, small-cell lung cancer) and HOTAIR rs1899663 (P = 0.03, male; P = 0.03, smoker) were associated with response to platinum-based chemotherapy. HOTTIP, CCAT2, H19, HOTAIR, MALATI, ANRIL genetic polymorphisms were significantly associated with lung cancer susceptibility or platinum-based chemotherapy response. They may be potential clinical biomarkers to predict lung cancer risk and platinum-based chemotherapy response.

Zhou T, Kim Y, MacLeod AR
Targeting Long Noncoding RNA with Antisense Oligonucleotide Technology as Cancer Therapeutics.
Methods Mol Biol. 2016; 1402:199-213 [PubMed] Related Publications
Recent annotation of the human transcriptome revealed that only 2 % of the genome encodes proteins while the majority of human genome is transcribed into noncoding RNAs. Although we are just beginning to understand the diverse roles long noncoding RNAs (lncRNAs) play in molecular and cellular processes, they have potentially important roles in human development and pathophysiology. However, targeting of RNA by traditional structure-based design of small molecule inhibitors has been difficult, due to a lack of understanding of the dynamic tertiary structures most RNA molecules adopt. Antisense oligonucleotides (ASOs) are capable of targeting specific genes or transcripts directly through Watson-Crick base pairing and thus can be designed based on sequence information alone. These agents have made possible specific targeting of "non-druggable targets" including RNA molecules. Here we describe how ASOs can be applied in preclinical studies to reduce levels of lncRNAs of interest.

Arun G, Diermeier S, Akerman M, et al.
Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss.
Genes Dev. 2016; 30(1):34-51 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Genome-wide analyses have identified thousands of long noncoding RNAs (lncRNAs). Malat1 (metastasis-associated lung adenocarcinoma transcript 1) is among the most abundant lncRNAs whose expression is altered in numerous cancers. Here we report that genetic loss or systemic knockdown of Malat1 using antisense oligonucleotides (ASOs) in the MMTV (mouse mammary tumor virus)-PyMT mouse mammary carcinoma model results in slower tumor growth accompanied by significant differentiation into cystic tumors and a reduction in metastasis. Furthermore, Malat1 loss results in a reduction of branching morphogenesis in MMTV-PyMT- and Her2/neu-amplified tumor organoids, increased cell adhesion, and loss of migration. At the molecular level, Malat1 knockdown results in alterations in gene expression and changes in splicing patterns of genes involved in differentiation and protumorigenic signaling pathways. Together, these data demonstrate for the first time a functional role of Malat1 in regulating critical processes in mammary cancer pathogenesis. Thus, Malat1 represents an exciting therapeutic target, and Malat1 ASOs represent a potential therapy for inhibiting breast cancer progression.

Jin C, Yan B, Lu Q, et al.
Reciprocal regulation of Hsa-miR-1 and long noncoding RNA MALAT1 promotes triple-negative breast cancer development.
Tumour Biol. 2016; 37(6):7383-94 [PubMed] Related Publications
Recent studies demonstrated that long noncoding RNAs (lncRNAs) have a critical role in the regulation of cancer progression and metastasis. However, little is known about the mechanism through which metastasis-associated lung adencarcinoma transcript 1 (MALAT1) exerts its oncogenic activity, and the interaction between MALAT1 and microRNA remains largely unknown. In the present study, we reported that MALAT1 was upregulated in triple-negative breast cancer (TNBC) tissues. Knockdown of MALAT1 inhibited proliferation, motility, and increased apoptosis in vitro. In vivo study indicated that knockdown of MALAT1 inhibited tumor growth and metastasis. Patients with high MALAT1 expression had poorer overall survival time than those with low MALAT1 expression. In addition, our findings demonstrate a reciprocal negative control relationship between MALAT1 and miR-1: downregulation of MALAT1 increased expression of microRNA-1 (miR-1), while overexpression of miR-1 decreased MALAT1 expression. Slug was identified as a direct target of miR-1. We proposed that MALAT1 exerted its function through the miR-1/slug axis. In summary, we proposed that MALAT1 may be a target for TNBC therapy.

Ma J, Wang P, Yao Y, et al.
Knockdown of long non-coding RNA MALAT1 increases the blood-tumor barrier permeability by up-regulating miR-140.
Biochim Biophys Acta. 2016; 1859(2):324-38 [PubMed] Related Publications
The blood-tumor barrier (BTB) forms a major obstacle in brain tumor therapy by preventing the delivery of sufficient quantities of therapeutic drugs. Long non-coding RNAs (lncRNAs) play important roles in both normal development and diseases including cancer. Here, we elucidated the expression of lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and defined its functional role in the regulation of BTB function as well as its possible molecular mechanisms. Our results proved that MALAT1 expression was up-regulated in brain microvessels of human glioma and glioma endothelial cells (GECs) which were obtained by co-culturing endothelial cells with glioma cells. Functionally, knockdown of MALAT1 resulted in an impairment and increased the permeability of BTB as well as decreased the expression of ZO-1, occludin and claudin-5 in GECs. Further, there was reciprocal repression between MALAT1 and miR-140, and miR-140 mediated the effects that MALAT1 knockdown exerted. Mechanistic investigations defined that nuclear factor YA (NFYA), a CCAAT box-binding transcription factor, was a direct and functional downstream target of miR-140, which was involved in the MALAT1 knockdown induced regulation of BTB function. Furthermore, NFYA could up-regulate the promoter activities and bind to the promoters of ZO-1, occludin and claudin-5 in GECs. Taken together, we have demonstrated the fact that knockdown of MALAT1 resulted in the increased permeability of BTB, which might contribute to establishing potential therapeutic strategies for human gliomas.

Yang H, Liu Z, Yuan C, et al.
Elevated JMJD1A is a novel predictor for prognosis and a potential therapeutic target for gastric cancer.
Int J Clin Exp Pathol. 2015; 8(9):11092-9 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Jumonji domain-containing protein 1A (JMJD1A) play a key role in the development and progression of several malignancies. The present study investigated the expression and clinical significance of JMJD1A in gastric cancer. JMJD1A was found to be upregulated in gastric cancer tissues and cell lines. Furthermore, the upregulated expression of JMJD1A was significantly correlated with the results of the invasion depth (P=0.006), lymph node metastatic status (P<0.001), and TNM stage (P<0.001). JMJD1A was also shown to be an independent prognostic predictor of overall survival (HR3.988; 95% CI 1.948-8.167; P<0.001) for patients with gastric cancer. In addition, in vitro experiment revealed that knockdown of JMJD1A expression inhibited the gastric cancer cell proliferation, and further study suggested that JMJD1A knockdown suppressed MAPK pathway via transcriptional downregulation the expression of long noncoding RNA MALAT1. Therefore, we speculated that JMJD1A-MALAT1-MAPK signaling might participate in the JMJD1A-induced cell proliferation of gastric cancer. Collectively, our data demonstrate for the first time that JMJD1A gene has an important regulatory role in gastric carcinogenesis, and could function as a novel prognostic indicator and a potential therapeutic target for gastric cancer.

Zhou X, Liu S, Cai G, et al.
Long Non Coding RNA MALAT1 Promotes Tumor Growth and Metastasis by inducing Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma.
Sci Rep. 2015; 5:15972 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
The prognosis of advanced oral squamous cell carcinoma (OSCC) patients remains dismal, and a better understanding of the underlying mechanisms is critical for identifying effective targets with therapeutic potential to improve the survival of patients with OSCC. This study aims to clarify the clinical and biological significance of metastasis-associated long non-coding RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in OSCC. We found that MALAT1 is overexpressed in OSCC tissues compared to normal oral mucosa by real-time PCR. MALAT1 served as a new prognostic factor in OSCC patients. When knockdown by small interfering RNA (siRNA) in OSCC cell lines TSCCA and Tca8113, MALAT1 was shown to be required for maintaining epithelial-mesenchymal transition (EMT) mediated cell migration and invasion. Western blot and immunofluorescence staining showed that MALAT1 knockdown significantly suppressed N-cadherin and Vimentin expression but induced E-cadherin expression in vitro. Meanwhile, both nucleus and cytoplasm levels of β-catenin and NF-κB were attenuated, while elevated MALAT1 level triggered the expression of β-catenin and NF-κB. More importantly, targeting MALAT1 inhibited TSCCA cell-induced xenograft tumor growth in vivo. Therefore, these findings provide mechanistic insight into the role of MALAT1 in regulating OSCC metastasis, suggesting that MALAT1 is an important prognostic factor and therapeutic target for OSCC.

Wang D, Ding L, Wang L, et al.
LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer.
Oncotarget. 2015; 6(38):41045-55 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
The Polycomb protein enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in advanced human prostate cancer (PCa), especially in lethal castration-resistant prostate cancer (CRPC). However, the signaling pathways that regulate EZH2 functions in PCa remain incompletely defined. Using EZH2 antibody-based RNA immunoprecipitation-coupled high throughput sequencing (RIP-seq), we demonstrated that EZH2 binds to MALAT1, a long non-coding RNA (lncRNA) that is overexpressed during PCa progression. GST pull-down and RIP assays demonstrated that the 3' end of MALAT1 interacts with the N-terminal of EZH2. Knockdown of MALAT1 impaired EZH2 recruitment to its target loci and upregulated expression of EZH2 repressed genes. Further studies indicated that MALAT1 plays a vital role in EZH2-enhanced migration and invasion in CRPC cell lines. Meta-analysis and RT-qPCR of patient specimens demonstrated a positive correlation between MALAT1 and EZH2 expression in human CRPC tissues. Finally, we showed that MALAT1 enhances expression of PRC2-independent target genes of EZH2 in CRPC cells in culture and patient-derived xenografts. Together, these data indicate that MALAT1 may be a crucial RNA cofactor of EZH2 and that the EZH2-MALAT1 association may provide a new avenue for development new strategies for treatment of CRPC.

Yao W, Bai Y, Li Y, et al.
Upregulation of MALAT-1 and its association with survival rate and the effect on cell cycle and migration in patients with esophageal squamous cell carcinoma.
Tumour Biol. 2016; 37(4):4305-12 [PubMed] Related Publications
The aim of this study is to investigate whether metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) can be used as a potential therapy target for human esophageal squamous cell carcinoma. MALAT-1 expression levels were detected in 137 paired EC samples and adjacent nonneoplastic tissues. Human esophageal carcinoma cell lines EC9706 and KYSE150 were transfected with MALAT-1 small interference RNA. Cell proliferation, migration/invasion ability, cell cycle, and apoptosis were assessed. MALAT-1 expressed higher levels in esophageal cancer tissues when compared with paired adjacent normal tissues. This high expression was associated with a decreased survival rate. MALAT-1 knockdown induced a decrease in proliferation-enhanced apoptosis, inhibited migration/invasion, and reduced colony formation and led to cell cycle arrest at the G2/M phase. These data indicates that MALAT-1 could be exploited for therapeutic benefit.

Jin C, Yan B, Lu Q, et al.
The role of MALAT1/miR-1/slug axis on radioresistance in nasopharyngeal carcinoma.
Tumour Biol. 2016; 37(3):4025-33 [PubMed] Related Publications
Recent studies demonstrated that long non-coding RNAs (lncRNAs) have a critical role in the regulation of cancer progression and metastasis. However, little is known whether lncRNA regulated nasopharyngeal carcinoma (NPC) cell radioresistance. In the present study, we found that MALAT1 was significantly upregulated in NPC cell lines and tissues. Knockdown of MALAT1 could sensitize NPC cells to radiation both in vitro and in vivo. Interestingly, we found that MALAT1 regulated radioresistance by modulating cancer stem cell (CSC) activity. Furthermore, we found that there was reciprocal repression between MALAT1 and miR-1, and slug was identified as a downstream target of miR-1. Taking these observations into consideration, we proposed that MALAT1 regulated CSC activity and radioresistance by modulating miR-1/slug axis, which indicated that MALAT1 could act as a therapeutic target for NPC patients.

Simms A, Jacob RP, Cohen C, Siddiqui MT
TROP-2 expression in papillary thyroid carcinoma: Potential Diagnostic Utility.
Diagn Cytopathol. 2016; 44(1):26-31 [PubMed] Related Publications
TROP-2 is a type I transmembrane glycoprotein which is over-expressed in various malignancies, and is related to epithelial cell adhesion molecule (EpCAM), also called TROP-1, gp40, and KSA. In this study, we evaluated TROP-2 expression in papillary thyroid carcinoma (PTC) and compared it to other thyroid neoplastic and non-neoplastic lesions. Immunohistochemical (IHC) evaluation for TROP-2 was performed on 137 thyroid fine needle aspiration (FNA) cell blocks (CB) which included classic PTC (64), follicular variant PTC (FVPTC) (10), anaplastic thyroid carcinoma (AC) (2), medullary carcinoma (MC) (8), follicular neoplasms (FN) (8), Hurthle cell neoplasms (HCN) (9), follicular lesion of uncertain significance (FLUS) (12), and benign thyroid nodule (BTN) (24). IHC for TROP-2 expression was also performed on 331 BTN and malignant tumor tissue sections in tissue microarray (TMA). Membranous staining in >5% of tumor cells was considered positive. TROP-2 stained 61 of 64 PTC CB, 7 of 10 FVPTC CB, and 9 of 12 FLUS CB. All other cases were negative for TROP-2. TROP-2 showed a sensitivity of 95.31% and specificity of 89% for classic PTC in FNA CB. In TMA samples, TROP-2 stained 54 of 60 classic PTC cases and hence showed a high sensitivity and specificity. All BTN in CB and TMA were negative. We conclude that TROP-2 is a highly sensitive and specific IHC marker for identifying classic PTC. TROP-2 may play an important role in diagnosing classic PTC, especially in equivocal cases. This study also identifies a strong role for TROP-2 in separating PTC from BTN.

Xiao H, Tang K, Liu P, et al.
LncRNA MALAT1 functions as a competing endogenous RNA to regulate ZEB2 expression by sponging miR-200s in clear cell kidney carcinoma.
Oncotarget. 2015; 6(35):38005-15 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Long non-coding RNA (lncRNAs) play a critical role in the development of cancers. LncRNA metastasis-associated lung adenocarcinoma transcript 1(MALAT1) has recently been identified to be involved in tumorigenesis of several cancers such as lung cancer, bladder cancer and so on. Here, we found that MALAT1 exist a higher fold change (Tumor/Normal) in clear cell kidney carcinoma (KIRC) from The Cancer Genome Atlas (TCGA) Data Portal and a negative correlation with miR-200s family. We further demonstrated MALAT1 promote KIRC proliferation and metastasis through sponging miR-200s in vitro and in vivo. In addition, miR-200c can partly reverse the MALAT1's stimulation on proliferation and metastasis in KIRC. In summary we unveil a branch of the MALAT1/miR-200s/ZEB2 pathway that regulates the progression of KIRC. The inhibition of MALAT1 expression may be a promising strategy for KIRC therapy.

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