长链非编码RNA-HOXA11-AS结合miR-124-3p调控整合素表达在胃癌侵袭转移中的机制研究

Our group found that the Single Nucleotide Polymorphisms(SNPs) within the binding site of miR-124-3p on integrin gene was significantly associated with the gastric cancer(GC) staging. Bioinformatics and initial functional experiment demonstrated that miR-124-3p could up-regulate the expression level of ITGB3 gene by targeting its 3’UTR region, then promoting the invasion and metastasis of GC. Previous studies have shown that long non-coding RNAs(lncRNAs) can competitively binding to microRNA(miRNA) as the form of competing endogenous RNAs(ceRNAs) and then affect the development of tumor. Our group combined the bioinformatics and microarry results, finding that HOXA11-AS can target miR-124-3p and had differential expression level between GC tissues with different invasion and metastasis degree. Based on previous research, we proposed " HOXA11-AS can competitively bind to miR-124-3p, and the latter could no longer up-regulate the expression of integrin gene, therefore inhibiting the invasion and metastasis of GC”. We will explore the mechanism that HOXA11-AS regulate miR-124-3p and subsequent regulation of the expression of integrin β3 as well as the effect on the invasion and metastasis of GC from the cellular and overall perspective. This study will provide a new direction to demonstrate the molecular mechanism of GC and to find potential molecular targets for prognosis and treatment of GC.

课题组前期研究发现，位于miR-124-3p与整合素基因结合位点内的SNP与胃癌分期有显著相关性，初步功能验证提示此miRNA可能通过结合整合素基因3’UTR区上调基因表达水平，促进胃癌的侵袭转移。新近研究提示lncRNA可作为ceRNA竞争性结合miRNA，影响肿瘤的发生发展。课题组通过生物信息学预测并结合lncRNA芯片结果，发现lncRNA-HOXA11-AS在不同侵袭转移程度的胃癌组织中存在差异表达，且其上存在miR-124-3p的结合靶点。课题组提出“HOXA11-AS可通过结合miR-124-3p，减弱后者对整合素基因的上调作用，减少整合素基因的转录，进而抑制胃癌细胞的侵袭转移”。本项目拟从细胞和整体水平深入探讨HOXA11-AS结合miR-124-3p，调控整合素基因表达，参与胃癌侵袭转移的分子机制，为胃癌的发生发展机制、预后判断分子标志物及临床治疗提供理论基础和实验依据。

胃癌是一个全球性的健康问题，全世界每年有超过一百万的新诊断病例。肿瘤对周围组织的侵袭和早期发生邻近及远端组织转移是导致胃癌预后差的主要原因，造成胃癌所致的死亡率居高不下。筛选新的胃癌侵袭与转移相关分子标志物，探索胃癌侵袭与转移的分子作用机制，并提供潜在的治疗干预靶点，具有重要的理论意义和应用价值。. 课题组前期研究发现，miR-124-3p与整合素结合位点内的SNP与胃癌侵袭与转移相关。同时，课题组通过生物信息学预测并结合lncRNA芯片结果，发现lncRNA-HOXA11-AS在不同侵袭转移程度的胃癌组织中存在差异表达，且其上存在miR-124-3p的结合靶点。本课题的研究内容是从细胞和整体水平深入探讨lncRNA-HOXA11-AS结合miR-124-3p，调控整合素表达，参与胃癌侵袭与转移的分子机制，为胃癌的发生发展机制、预后判断分子标志物及临床治疗提供理论基础和实验依据。. 本课题研究结果显示，miR-124-3p表达水平改变可以调控ITGB3和整合素β3表达，miR-124-3p/ITGB3/整合素β3参与了胃癌的增殖、迁移和侵袭：miR-124-3p表达上调，抑制ITGB3表达，整合素β3表达减少，抑制胃癌侵袭与转移，miR-124-3p通过调控ITGB3和整合素β3在胃癌中发挥肿瘤抑制功能。LncRNA-HOXA11-AS可充当miR-124-3p的分子海绵，与miR-124-3p竞争性结合，上调了ITGB3基因的表达，整合素β3表达增加，促进胃癌的发生发展。. 本课题针对胃癌这一严重危害身体健康和导致社会沉重经济负担的重大疾病，从lncRNA、miRNA、整合素及肿瘤细胞增殖迁移相互作用方面研究胃癌侵袭与转移的分子机制，为进一步揭示胃癌侵袭与转移机制提供了一条值得探索的途径，也为胃癌的治疗和预后判断提供了新的思路。