Up-regulation of long noncoding RNA MALAT1 contributes to proliferation and metastasis in esophageal squamous cell carcinomaReport as inadecuate




Up-regulation of long noncoding RNA MALAT1 contributes to proliferation and metastasis in esophageal squamous cell carcinoma - Download this document for free, or read online. Document in PDF available to download.

Journal of Experimental and Clinical Cancer Research

, 34:7

First Online: 22 January 2015Received: 02 November 2014Accepted: 04 January 2015DOI: 10.1186-s13046-015-0123-z

Cite this article as: Hu, L., Wu, Y., Tan, D. et al. J Exp Clin Cancer Res 2015 34: 7. doi:10.1186-s13046-015-0123-z

Abstract

BackgroundMetastasis Associated Lung Adenocarcinoma Transcript 1 MALAT1 has been demonstrated to be an important player in various human malignancies; it is thought to promote tumor growth by cell cycle regulating. However, the roles of MALAT1 in esophageal squamous cell carcinomaESCC, and the mechanisms involved in cell cycle regulation remain poorly understood. Moreover, the factors contributing to its up-regulation in tumor tissues are still largely unclear.

MethodsExpression of MALAT1 was determined from cell lines and clinical samples by qRT-PCR. The effects of MALAT1 knockdown on cell proliferation, cell cycle, apoptosis, migration, and invasion were evaluated by in vitro and in vivo assays. The potential protein expression changes were investigated by Western-blotting. The methylation status of the CpG island in the MALAT1 promoter was explored by bisulfite sequencing, while the copy numbers in tumor tissues and blood samples were detected by a well-established AccuCopy method.

ResultsMALAT1 was over-expressed in 46.3% of ESCC tissues, mostly in the high-stage tumor samples. Enhanced MALAT1 expression levels were positively correlated with clinical stages, primary tumor size, and lymph node metastasis. Inhibition of MALAT1 suppressed tumor proliferation in vitro and in vivo, as well as the migratory and invasive capacity. MALAT1 depletion also induced G2-M phase arrest and increased the percentage of apoptotic cells. Western-blotting results implicated that the ATM-CHK2 pathway which is associated with G2-M arrest was phosphorylated by MALAT1 knockdown. No effects of CpG island methylation status on MALAT1 expression were found, whereas amplification of MALAT1 was found in 22.2% of tumor tissues, which correlated significantly with its over-expression. However, neither association between tissue copy number amplification and germline copy number variation, nor correlation between germline copy number variation and ESCC risk were identified in the case–control study.

ConclusionsOur data suggest that MALAT1 serves as an oncogene in ESCC, and it regulates ESCC growth by modifying the ATM-CHK2 pathway. Moreover, amplification of MALAT1 in tumor tissues may play an important role for its up-regulation, and it seems that the gene amplification in tumor tissues emerges during ESCC progression, but is not derived from germline origins.

KeywordsLong noncoding RNA MALAT1 Esophageal cancer Copy number Cell cycle arrest AbbreviationsESCCEsophageal squamous cell carcinoma

NSCLCNon-small cell lung cancer

CNVCopy number variation

lncRNALong noncoding RNA

cDNAComplementary DNA

qRT-PCRQuantitative Reverse Transcription-PCR

HOTAIRHOX Transcript Antisense RNA

MEG3Maternally expressed 3

GAS5Growth arrest-specific 5

MALAT1Metastasis associated lung adenocarcinoma transcript 1

LBLysogeny broth

X-gal5-Bromo-4-chloro-3-indolyl β-D-galactopyranoside

IPTGIsopropyl β-D-1-Thiogalactopyranoside

ATMAtaxia telangiectasia-mutated kinase

CHK2Checkpoint kinase 2

CDC25CCell division cycle 25C

CDK1Cyclin-dependent kinase 1

CDH1Cadherin 1

GAPDHGlyceraldehyde-3-phosphate dehydrogenase

Electronic supplementary materialThe online version of this article doi:10.1186-s13046-015-0123-z contains supplementary material, which is available to authorized users.

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Author: Liwen Hu - Yuanyuan Wu - Deli Tan - Hui Meng - Kai Wang - Yun Bai - Kang Yang

Source: https://link.springer.com/







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