LncRNA调控PI3K-Akt-mTOR信号通路在胃癌发生中的作用机制及生物标志研究

Gastric cancer which causes serious damage to human health, however, its pathogenesis remains unclear. The role of long non-coding RNA (lncRNA) is becoming a new hot spot in this field. Our previous study has found that two key lncRNAs—UCA1 and LOC101928316, which were related with gastric cancer by high-throughput screening and The Cancer Genome Atlas (TCGA) database analysis. Expand tissue samples study found that the two key lncRNAs not only has obviously changed in the early gastric cancer, but also significantly associated with gastric cancer progression. In addition, our cell research also gets the same conclusion. Furthermore, combining the mRNA expression profile analysis and cell experiments, we found that the two key lncRNAs may regulate the PI3K-Akt-mTOR signaling pathway, but the mechanism remains to be further clarified. In this study, we construct the UCA1 and LOC101928316 regulation network of PI3K-Akt-mTOR signaling pathway by cell experiments, and also combine the animal model experiments to clarify the two key lncRNAs roles of regulate PI3K-Akt-mTOR signaling pathway in the development of gastric cancer. Finally, we use large population-based study to further investigate UCA1 and LOC101928316 and their related molecules as biomarkers for gastric cancer early diagnosis, assessment and prognostic. The results will supply the evidence for further revealing the molecular mechanisms and provide a basis for prevention and treatment of gastric cancer.

胃癌严重危害人类健康，其发病机制需深入探讨，lncRNA是目前备受关注的热点之一。我们前期通过高通量筛选结合TCGA数据库分析，发现两个胃癌关键lncRNA：UCA1和LOC101928316。扩大组织样本研究发现二者不仅在胃癌早期发生明显改变，且与胃癌进展程度显著相关，细胞研究也获得同样结论，进一步结合mRNA表达谱分析和细胞预实验发现这两个lncRNA可能通过对PI3K-Akt-mTOR信号通路的调控发挥作用，但机制有待深入阐明。本研究应用细胞模型，构建UCA1和LOC101928316对PI3K-Akt-mTOR通路的调控网络，结合动物模型，阐明这两个lncRNA调控PI3K-Akt-mTOR通路在胃癌发生发展中的作用，最后通过大样本人群研究，探讨UCA1和LOC101928316及相关分子作为胃癌早期诊断、评估和预后判断生物标志的可能。研究为进一步揭示胃癌分子机制及其防治提供依据。

胃癌作为威胁人类健康的恶性肿瘤，其死亡率位列所有恶性肿瘤第二。研究胃癌的病因学和发病机制，针对胃癌发生发展筛选新生物标志，对控制胃癌发展态势，推进胃癌防治至关重要。本项目旨在阐明胃癌关键lncRNAs调控PI3K-Akt-mTOR信号通路在胃癌发生发展中的作用，探讨关键lncRNAs作为胃癌早期诊断、评估和预后判断生物标志的可能性。围绕研究目标，本项目首先通过基因芯片筛选胃癌相关关键lncRNAs，并与国际肿瘤数据库胃癌测序数据相对比，综合分析lncRNAs在胃癌中的表达及其与临床特征、预后的相关性，构建胃癌lncRNA-mRNA共表达网络、ceRNA调控网络，建立有效lncRNAs诊断与预后的危险评分模型，并在人群组织样本中进行验证。进一步应用细胞模型和动物模型探讨lncRNAs的生物学功能及调控机制，发现lncRNA UCA1、LOC101928316可通过调控PI3K-Akt-mTOR通路影响胃癌细胞的增殖、凋亡和侵袭迁移能力，阐明UCA1和LOC101928316在胃癌发生发展中的作用机制。最后，在人群中进行lncRNAs表达及生物标志研究，最终发现UCA1等7种lncRNAs与胃癌的分化、分期以及淋巴转移等密切相关，可作为胃癌早期诊断、评估和预后判断生物标志。研究结果对明确胃癌发生发展的机理具有重要意义，胃癌新候选生物标志的发现可为进一步促进人群早期预警及胃癌的主动预防提供科学依据，也为建立以生物标志物为基础的危险度评价奠定坚实基础。