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

Journal of Experimental & Clinical Cancer Research

Kang Yang¹  Yun Bai²  Kai Wang²  Hui Meng²  Deli Tan¹  Yuanyuan Wu²  Liwen Hu¹ 

[1] Department of Cardiothoracic Surgery, Southwest Hospital, Third Military Medical University, Gaotanyan St., Shapingba District, Chongqing, People’s Republic of China;Department of Medical Genetics, College of Basic Medical Science, Third Military Medical University, Gaotanyan St., Shapingba District, Chongqing, People’s Republic of China

关键词: Cell cycle arrest;    Copy number;    Esophageal cancer;    MALAT1;    Long noncoding RNA;   

Others  :  1133641
DOI  :  10.1186/s13046-015-0123-z

 received in 2014-11-02, accepted in 2015-01-04,  发布年份 2015

【 摘 要 】

Background

Metastasis 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 carcinoma(ESCC), 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.

Methods

Expression 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^TM method.

Results

MALAT1 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.

Conclusions

Our 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.

【 授权许可】

   
2015 Hu et al.; licensee Biomed Central.

【 图 表 】

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