Promoter hypermethylation-mediated downregulation of tumor suppressor gene SEMA3B and lncRNA SEMA3B-AS1 correlates with progression and prognosis of esophageal squamous cell carcinoma
Promoter hypermethylation-mediated downregulation of tumor suppressor gene SEMA3B and lncRNA SEMA3B-AS1 correlates with progression and prognosis of esophageal squamous cell carcinoma
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启动子高甲基化介导的抑癌基因SEMA3B和lncRNA SEMA3B-AS1的下调与食管鳞状细胞癌的进展和预后相关
DOI：
10.1007/s10585-019-09964-3
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发表时间：
2019-06-01
影响因子：
4
通讯作者：
Guo, Wei
中科院分区：
文献类型：
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作者：
Dong, Zhiming;Liang, Xiaoliang;Guo, Wei
在食管鳞状细胞癌(ESCC)中发现了染色体3p21.3上频繁缺失的抑癌基因。信号素3B(Semaphorin 3B，SEMA3B)是一种候选抑癌基因，位于3p21.3，在多种肿瘤中经常失活。然而，SEMA3B及其反义长非编码RNA(LncRNA)SEMA3B-AS1在食管癌发生中的作用和失活机制尚未完全阐明。本研究旨在探讨SEMA3B和SEMA3B-AS1在食管癌发生和预后中的作用、表观失活机制及其预后价值。SEMA3B和SEMA3B-AS1在食道癌细胞和食管癌组织中表达频繁下调，其表达水平与食管鳞癌的TNM分期和淋巴结转移有关。SEMA3B和SEMA3B-AS1在启动子区域具有相同的CpG岛，两者的表达可能受启动子甲基化状态的调控。此外，转录因子Sp1激活了SEMA3B或SEMA3B-AS1的转录，SEMA3B和SEMA3B-AS1启动子的甲基化影响了Sp1的结合能力。此外，SEMA3B和SEMA3B-AS1的过表达抑制了体外培养的食道癌细胞的活性和侵袭力。SEMA3B-AS1影响SEMA3B的蛋白表达。SEMA3B或SEMA3B-AS1的表达和启动子甲基化状态与ESCC患者的生存相关。因此，这些发现表明SEMA3B和SEMA3B-AS1可能作为肿瘤抑制因子，并可能成为抗肿瘤治疗的潜在靶点。
Frequent deletions of tumor-suppressor genes at chromosome 3p21.3 have been detected in esophageal squamous cell carcinoma (ESCC). As a candidate tumor suppressor gene, semaphorin 3B (SEMA3B) is located at 3p21.3 and is frequently inactivated in several tumors. However, the role and inactivation mechanisms of SEMA3B and its antisense long non-coding RNA (lncRNA) SEMA3B-AS1 in the carcinogenesis of ESCC have not been fully elucidated. The present study was conducted to investigate the role, epigenetic inactivation mechanisms, and prognostic value of SEMA3B and SEMA3B-AS1 in ESCC tumorigenesis and prognosis. Frequent downregulation of SEMA3B and SEMA3B-AS1 was detected in esophageal cancer cells and ESCC tissues, and the expression level of SEMA3B and SEMA3B-AS1 in ESCC tissues was correlated with TNM stage and lymph node metastasis. SEMA3B and SEMA3B-AS1 shared the same CpG island in the promoter region and the expression of both genes might be regulated by the promoter methylation status. Furthermore, transcription factor Sp1 activated SEMA3B or SEMA3B-AS1 transcription and the promoter hypermethylation of SEMA3B and SEMA3B-AS1 influenced Sp1 binding ability. Moreover, over-expression of SEMA3B and SEMA3B-AS1 suppressed the viability and invasion of esophageal cancer cells in vitro. SEMA3B-AS1 influenced the protein expression of SEMA3B. SEMA3B or SEMA3B-AS1 expression and promoter methylation status were correlated with ESCC patients’ survival. Thus, these findings suggest that SEMA3B and SEMA3B-AS1 may act as tumor suppressors and may serve as potential targets for antitumor therapy.