长非编码RNA LINC00707调控mRNA稳定性促进胃癌增殖和转移的机制研究

The morbidity and mortality of gastric cancer (GC) remained high while its pathogenesis was still not clear. Long noncoding RNAs (lncRNAs) were gradually demonstrated as one of GC-associated regulatory molecules and involved in regulating GC malignant biological behavior. Our preliminary study found that LINC00707 was possibly activated by transcription factor SP1, and significantly up-regulated in GC; Overexpressed LINC00707 was also validated to bind with RNA-binding protein HuR, promoting GC cell malignant proliferation and migration. In view of the definite mechanism “HuR post-transcriptionally binding to mRNA 3’UTR and increasing mRNA stability” and the unverified mechanism “LINC00707 regulating mRNA stability in GC”, our new study will conduct following experiments from three aspects, including clinical tissue specimens, cells and animal model. We will keep on confirming the function and clinical significance of LINC00707 in GC; The common target genes of LINC00707 and HuR will be affirmed and the molecular mechanism of LINC00707-HuR regulating mRNA stability should be further explored. This study will illuminate the molecular mechanism of LINC00707 regulating mRNA stability, and provide new theories in clinical diagnosis and therapies.

胃癌的发病率和死亡率高，但其病因仍未完全明确。研究已证实lncRNAs是胃癌功能的重要调控分子之一，参与胃癌恶性生物学过程。项目组前期研究发现，LINC00707可能受SP1激活在胃癌中异常高表达，与HuR蛋白绑定，促进胃癌细胞增殖和转移。鉴于“HuR与靶mRNA 3’UTR区结合并提高其稳定性的机制明确；LINC00707在胃癌中调控mRNA稳定性的分子机制尚未明确”的研究背景，故本项目拟从组织、细胞和动物实验三点着手，继续验证LINC00707在胃癌中癌基因的功能和临床意义，探索LINC00707和HuR下游共同调控的靶基因，以及“LINC00707-HuR”是否结合于靶mRNA 3’UTR区并提高其稳定性。本研究旨在阐明LINC00707在胃癌中调控mRNA稳定性的分子机制，为胃癌的早期诊断提供部分新的实验和理论依据。

本项目组结合“胃癌的发病率和死亡率高，病因未完全明确”的中国国情，以及 “lncRNAs是胃癌功能的重要调控分子之一，参与胃癌恶性生物学过程”的研究背景，从临床组织标本、细胞、动物实验三点着手，验证长非编码RNA LINC00707在胃癌中癌基因的功能和临床意义，并深入探讨LINC00707调控mRNA稳定性的分子机制。本项目通过逐层筛选发现LINC00707在胃癌中异常高表达，并与胃癌患者的肿瘤大小、分期、淋巴结转移以及不良预后相关。在胃癌细胞中，LINC00707可与RNA结合蛋白HuR绑定，“LINC00707-HuR”复合体进一步结合在靶基因VAV3和F11R mRNAs 的3’UTR区，提高其mRNAs的稳定性，进一步促进胃癌细胞的增殖和转移。本研究的科学意义在于：首次阐明并揭示长非编码RNA LINC00707在胃癌中调控mRNA稳定性的分子机制，具有一定的创新性；同时本研究进一步丰富了lncRNAs调控胃癌发生发展的分子机制，为胃癌的早期诊断提供了部分新的实验和理论依据。