Up-regulation of long noncoding RNA MALAT1 contributes to proliferation and metastasis in esophageal squamous cell carcinoma.
Up-regulation of long noncoding RNA MALAT1 contributes to proliferation and metastasis in esophageal squamous cell carcinoma.
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长非编码RNA MALAT1的上调有助于食管鳞状细胞癌的增殖和转移
DOI：
10.1186/s13046-015-0123-z
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发表时间：
2015-01-22
期刊：
影响因子：
--
通讯作者：
Yang K
中科院分区：
文献类型：
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作者：
Hu L;Wu Y;Tan D;Meng H;Wang K;Bai Y;Yang K
研究背景转移相关肺腺癌转录本1(MALAT1)在多种人类恶性肿瘤中起重要作用，被认为通过细胞周期调节促进肿瘤生长。然而，MALAT1在食管鳞癌(ESCC)中的作用以及参与细胞周期调控的机制尚不清楚。此外，导致MALAT1在肿瘤组织中表达上调的因素在很大程度上仍不清楚。方法采用qRT-PCR方法检测MALAT1在细胞系和临床标本中的表达。通过体外和体内实验评价MALAT1基因敲除对细胞增殖、细胞周期、细胞凋亡、迁移和侵袭的影响。Western-blotting检测可能的蛋白表达变化。用亚硫酸氢盐测序法检测MALAT1启动子CpG岛的甲基化状态，用成熟的AccuCopyTM方法检测肿瘤组织和血液标本中的拷贝数。结果MALAT1在46.3%的ESCC组织中高表达，且多见于高分期肿瘤组织。MALAT1表达增强水平与临床分期、原发肿瘤大小和淋巴转移呈正相关。抑制MALAT1抑制肿瘤的体内外增殖，抑制肿瘤的迁移和侵袭能力。MALAT1缺失还可诱导细胞周期停滞于G2/M期，增加细胞凋亡率。Western-blotting结果表明，与G2/M期停滞相关的ATM-Chk2通路被MALAT1基因敲除后被磷酸化。未发现CpG岛甲基化状态对MALAT1表达的影响，而MALAT1在22.2%的肿瘤组织中扩增，这与其过度表达显著相关。然而，在病例对照研究中，未发现组织拷贝数扩增与生殖系拷贝数变异之间的关联，也未发现生殖系拷贝数变异与ESCC风险之间的相关性。结论MALAT1基因可能是ESCC中的一个癌基因，它通过修改ATM-Chk2途径来调节ESCC的生长。此外，MALAT1在肿瘤组织中的扩增可能在其上调中起重要作用，似乎肿瘤组织中的基因扩增是在ESCC进展过程中出现的，但不是源于胚系来源。
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 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.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 byin vitroandin vivoassays. 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 AccuCopyTMmethod.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 proliferationin vitroandin 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.
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