Aberrant methylation-mediated downregulation of lncRNA SSTR5-AS1 promotes progression and metastasis of laryngeal squamous cell carcinoma
Aberrant methylation-mediated downregulation of lncRNA SSTR5-AS1 promotes progression and metastasis of laryngeal squamous cell carcinoma
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DOI：
10.1186/s13072-019-0283-8
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发表时间：
2019-06-13
影响因子：
3.9
通讯作者：
Meng, Wenxia
中科院分区：
文献类型：
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作者：
Wang, Baoshan;Zhao, Lei;Meng, Wenxia
喉鳞状细胞癌（Laryngeal squamous cell carcinoma，LSCC）是最常见的恶性肿瘤之一，预后差.积累的证据已经确定了重要的作用，长的非编码RNA（lncRNA）在各种癌症类型的启动和发展，但是，全球lncRNA的表达谱转移性喉鳞癌是limited.ResultsIn本研究中，我们筛选lncRNA的表达谱在晚期喉鳞癌患者配对的肿瘤组织和相应的正常组织的微阵列。我们确定了许多差异表达的转录本，并在扩大样本中的转录本表达的必要验证后，我们实验验证了显着的低表达基因，SSTR 5，及其反义lncRNA，SSTR 5-AS 1的表达模式。SSTR 5在喉鳞癌组织和喉癌细胞中表达下调。SSTR 5基因启动子区CpG位点的异常甲基化和组蛋白失活修饰的积累可能是其失活的表观遗传学机制。SSTR 5-AS 1可能在喉鳞癌中发挥抗肿瘤作用，其作用可能与SSTR 5相同的CpG位点的高甲基化有关。SSTR 5-AS 1抑制喉癌细胞增殖、迁移和侵袭。SSTR 5-AS 1通过与MLL 3相互作用增加MLL 3和H3 K4 me 3在SSTR 5启动子区的富集，并进一步诱导SSTR 5的转录。此外，SSTR 5-AS 1与TET 1相互作用并将TET 1招募到其靶基因E-cadherin上，从而激活TET 1的表达。结论这些研究结果表明，所鉴定的lncRNA和mRNA可能是转移性喉鳞癌的潜在生物标志物，SSTR 5-AS 1可能作为肿瘤抑制剂以及抗肿瘤治疗的潜在生物标志物。
BackgroundLaryngeal squamous cell carcinoma (LSCC) is among the most common malignant tumors with poor prognosis. Accumulating evidences have identified the important roles of long noncoding RNAs (lncRNAs) in the initiation and progression of various cancer types; however, the global lncRNAs expression profile for metastatic LSCC is limited.ResultsIn the present study, we screen expression profiles of lncRNAs in advanced LSCC patients with paired tumor tissues and corresponding normal tissues by microarrays. We identify numerous differentially expressed transcripts, and after the necessary verification of the transcripts expression in expanded samples, we experimentally validate the expression patterns of the remarkable low expressed gene, SSTR5, and its antisense lncRNA, SSTR5-AS1. Downregulation of SSTR5 is detected in LSCC tissues and laryngeal carcinoma cells. Aberrant DNA hypermethylation of the CpG sites clustered in the exon 1 and accumulation of inactive histone modifications at SSTR5 promoter region may be epigenetic mechanisms for its inactivation in LSCC. SSTR5-AS1 may play antitumor role in LSCC and may be regulated by the hypermethylation of the same CpG sites with SSTR5. SSTR5-AS1 inhibits laryngeal carcinoma cells proliferation, migration, and invasion. SSTR5-AS1 increases the enrichment of MLL3 and H3K4me3 at the promoter region of SSTR5 by interacting with MLL3 and further induces the transcription of SSTR5. Furthermore, SSTR5-AS1 interacts with and recruits TET1 to its target gene E-cadherin to activate its expression.ConclusionThese findings suggest that the identified lncRNAs and mRNAs may be potential biomarkers in metastatic LSCC, and SSTR5-AS1 may act as a tumor suppressor as well as a potential biomarker for antitumor therapy.