长链非编码RNA SGOL1-AS1下调在胃癌细胞增殖及染色体不稳定性中的作用及其机制

lncRNAs have been shown to play pivotal roles in tumorigenesis and tumor progression. Our recent data demonstrated that antisens lncRNA SGOL1-AS1 was significally down-regulated in compared with matched normal tissues. Functional studies revealed that SGOL1-AS1 knockdown promoted GC cell proliferation and increased the cells of G2/M phase. We further revealed that SGOL1-AS1 negatively regulated SGOL1 expression, while MYC transactivated both SGOL1 and SGOL1-AS1. In addition, SGOL1-AS1 was regulated by DNA methylation. Based on these preliminary results, we will first validate MYC-induced transcription of both SGOL1 and SGOL1-AS1. Then, we will determine whether SGOL1-AS1 blocks MYC-mediated SGOL1 transcription and influences SGOL1 mRNA stability. The third, we will investigate the mechanism of SGOL1 down-regulation in GC and the effects of its downregulation on cell proliferation,mitosis and chromsome instability (CIN). The corrections between SGOL1-AS1/SGOL1 and clinical characteristics including GC prognosis will also be investigated. In conclusion, our current study is designed to clarify the function of SGOL1-AS1 and to investigate reciprocal regulation of MYC, SGOL1-AS1 and SGOL1 in GC. It will provide the new evidences to clarify the mechanisms of GC pathogenesis and develop valuable markers of gastric cancer prognosis.

lncRNA在肿瘤的发生、发展中起着重要作用。本课题组前期发现：反义lncRNA SGOL1-AS1在胃癌中显著下调；下调SGOL1-AS1促进胃癌细胞增殖、诱导G2/M期阻滞；SGOL1-AS1负调控正义编码基因SGOL1表达；MYC活化SGOL1及反义链SGOL1-AS1启动子；SGOL1-AS1表达受甲基化调控。本项目拟证实MYC激活SGOL1及SGOL1-AS1转录；研究SGOL1-AS1是否阻断MYC诱导的SGOL1基因转录；阐明SGOL1-AS1是否影响SGOL1 mRNA稳定性；阐明胃癌SGOL1-AS1下调机制及其下调在胃癌细胞增殖、有丝分裂及CIN中的作用；研究SGOL1-AS1及SGOL1的临床意义。上述研究将阐明SGOL1-AS1的生物学功能及MYC/SGOL1-AS1/SGOL1调控机制，可望为阐明胃癌发病机制提供新的依据，并有望为胃癌预后判断提供新的标志物。

近年来胃癌治疗效果仍然不容乐观，究其根本原因在于人们对胃癌等肿瘤发生发展的规律和机制认识不足。本研究中我们发现lncRNA SGOL1-AS1在胃癌中显著下调，且其低水平表达与肿瘤进展以及患者的预后差相关；揭示了SGOL1-AS1抑制胃癌的增殖、生长、细胞异常分裂及CIN，并且可抑制胃癌的侵袭与转移，增强胃癌对化疗药物的敏感性；证实了转录因子MYC可与SGOL1启动子及SGOL1-AS1启动子相结合，促进SGOL1、SGOL1-AS1的转录，而SGOL1-AS1抑制MYC与SGOL1启动子结合，下调SGOL1的表达；证明在胃癌组织中SGOL1-AS1启动子存在高甲基化，甲基化修饰抑制MYC结合SGOL1-AS1启动子的能力导致SGOL1-AS1转录水平降低；证实SGOL1-AS1可与PTBP1蛋白结合，且通过PTBP1促进TGFβ1/2 mRNA降解，从而达到抑制TGFβ信号通路，抑制胃癌肿瘤细胞的增、侵袭与迁移的能力。本研究揭示了SGOL1-AS1在胃癌发生发展中的作用及机制，为阐明胃癌发病机制及转移机制提供新的理论依据。并且我们证实SGOL1-AS1可作为胃癌外周血诊断标志物，可望应用于胃癌临床辅助诊断，具用重要的临床应用前景。