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Role of metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) in pancreatic cancer.

ABSTRACT: Metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) is a long non-coding RNA (lncRNA) that is a negative prognostic factor for patients with pancreatic cancer and several other tumors. In this study, we show that knockdown of MALAT-1 in Panc1 and other pancreatic cancer cell lines decreases cell proliferation, survival and migration. We previously observed similar results for the lncRNAs HOTTIP and HOTAIR in Panc1 cells; however, RNAseq comparison of genes regulated by MALAT-1 shows minimal overlap with HOTTIP/HOTAIR-regulated genes. Analysis of changes in gene expression after MALAT-1 knockdown shows that this lncRNA represses several tumor suppressor-like genes including N-myc downregulated gene-1 (NDRG-1), a tumor suppressor in pancreatic cancer that is also corepressed by EZH2 (a PRC2 complex member). We also observed that Specificity proteins Sp1, Sp3 and Sp4 are overexpressed in Panc1 cells and Sp knockdown or treatment with small molecules that decrease Sp proteins expression also decrease MALAT-1 expression. We also generated Kras-overexpressing p53L/L;LSL-KrasG12DL/+;p48Cre+/- (p53L/L/KrasG12D) and p53L/+;LSLKrasG12DL/+;p48Cre+/- (p53L/+/KrasG12D) mice which are p53 homo- and heterozygous, respectively. These mice rapidly develop pancreatic ductal adenocarcinoma-like tumors and were crossed with MALAT-1-/- mice. We observed that the loss of one or two MALAT-1 alleles in these Ras overexpressing mice does not significantly affect the time to death; however, the loss of MALAT-1 in the p53-/+ (heterozygote) mice slightly increases their lifespan.

SUBMITTER: Cheng Y

PROVIDER: S-EPMC5794178 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Role of metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) in pancreatic cancer.

Cheng Yating Y Imanirad Parisa P Jutooru Indira I Hedrick Erik E Jin Un-Ho UH Rodrigues Hoffman Aline A Leal de Araujo Jeann J Morpurgo Benjamin B Golovko Andrei A Safe Stephen S

PloS one 20180201 2

Metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) is a long non-coding RNA (lncRNA) that is a negative prognostic factor for patients with pancreatic cancer and several other tumors. In this study, we show that knockdown of MALAT-1 in Panc1 and other pancreatic cancer cell lines decreases cell proliferation, survival and migration. We previously observed similar results for the lncRNAs HOTTIP and HOTAIR in Panc1 cells; however, RNAseq comparison of genes regulated by MALAT-1 shows ...[more]

PMID: 29389953

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is highly malignant due to its late diagnosis and early metastasis. Lung metastasis of PDAC occurs in a significant number of diagnosed patients and represents high severity of disease and poor clinical outcome. However, the molecular regulation of lung metastasis of PDAC is still not fully understood. Tumor-associated macrophages (TAMs) have recently been found to play an important role in cancer initiation, proliferation, progression, and metastasis. The proliferation, differentiation, and polarization of macrophages has been shown to be regulated by interleukin 1β (IL-1β), which is generated by NLR family pyrin domain containing 3 (NLRP3)-induced formation of inflammasome. Herein we investigated whether NLRP3 plays a role in lung metastasis of PDAC through regulation of macrophage polarization.MethodsGene profiles for NLRP3 (+/+) and NLRP3 (-/-) macrophages obtained from the Gene Expression Omnibus (GEO) public database were compared and analyzed for altered genes related to macrophage polarization. The regulation of macrophage polarization by NLRP3 was examined in a coculture system with naïve NLRP3 (+/+) or NLRP3 (-/-) macrophages and PDAC cells. Cell growth was analyzed by a Cell Counting Kit-8 (CCK-8) assay. Cell invasiveness and migratory potential were analyzed by transwell cell invasion assay and cell migration assay, respectively. PDAC formation and lung metastasis were analyzed in a mouse model of PDAC with and without NLRP3 knockout.ResultsGEO database analysis revealed significant alteration in genes that regulate macrophage polarization in NLRP3-depleted macrophages. NLRP3-depletion in macrophages seemed to favor an M1/M2b polarization. In vitro, the presence of NLRP3 in macrophages led to M2a/c/d TAM-like polarization when they were cocultured with PDAC cells. Conversely, NLRP3 depletion in macrophages led to M1/M2b polarization when they were cocultured with PDAC cells. NLRP3-depletion significantly inhibited tumor growth and stage progression in a mouse model of PDAC and significantly reduced the occurrence of lung metastasis.ConclusionsOur results suggested that NLRP3 activation in TAM enhanced lung metastasis of PDAC through regulation of TAM polarization.

Project description:Abstract:Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non coding RNA (lncRNA) present in serum, is an important biomarker for detecting hepatocellular carcinoma (HCC). However, there are some shortcomings in current detection methods. So developing other novel MALAT1 detection methods is necessary. Electrochemical biosensors using different types of nanomaterials with various advantages may provide a suitable method for detection. Here, a new strategy for MALAT1 detection was proposed based on polyhedral nanogold-polyamide-amine dendrimers (PNG-PAMAMs). The SWCNH/Au composite was used as a capture probe immobilization matrix, and PNG-PAMAM was used as a trace label for the detection probe (DP). The strategy takes advantage of the ability of the surface of PNG to bind a capture probe whose sequence contains (GGG)3 trimer that can bind DNAzyme hemin. Moreover, PNG may carry abundant horseradish peroxidases (HRPs) to block excess nonspecific adsorption sites, with synergistic hemin catalysis. The results show that the biosensor provides ultrasensitive detection of MALAT1 with a remarkable catalytic effect. The enhanced biosensor has a detection limit of 0.22 fmol·mL-?1 for MALAT1, and the linear calibration of the biosensor ranged from 1 fmol·mL-?1 to 100?pmol·mL-?1. In addition, the electrochemical biosensor has desirable qualities compared to other detectors; for instance, it is inexpensive, highly stable, and sensitive and has good reproducibility. This assay was also successfully applied to the detection of MALAT1 in serum samples, demonstrating that the technology has potential application in the detection of MALAT1 for clinical HCC diagnosis. Graphical Abstract:The schematic presentation ilustrates MALATI detection by biosensor with differential pulse stripping voltammetry. Polyhedral nanogold-PAMAM/horseradish peroxidases (PNG-PAMAM/HRP) detection probe with DNAzyme (hemin) sites was applied to determine MALATI. Signal was amplified by hemin/HRP/H2O2 catalytic system.

Dataset Information

Role of metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) in pancreatic cancer.

Publications

Role of metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) in pancreatic cancer.

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