长链非编码RNA-TUSC7在胃癌中的抑癌作用及机制研究

By using microarray analysis, we found that a variety of long non-coding RNA (lncRNAs) were dysregulated in gastric cancer (GC) tissues and adjacent normal tissues, in which the expression of tumor suppressor candidate 7 (TUSC7) in tumor tissues was significantly lower than that in adjacent normal tissues. Potential relationship between tumor TUSC7 levels and some clinicopathological features was found, and low TUSC7 expression had a significantly poorer prognosis than those with high TUSC7 expression. In addition, overexpression of TUSC7 inhibits growth of gastric cancer in vitro and in vivo. Furthermore, we showed that TUSC7 may be a direct transcriptional target of p53 through interaction with the putative p53 response element in the upstream region of TUSC7. By using bioinformatics analysis combined with cellular functional experiments, we found the potential target molecules of TUSC7, including protein-coding genes and miRNAs. The actual mechanism needs to be further explored. Based on these results, we plan to investigate the biological function of TUSC7 in the onset and development of GC by means of gene cloning, RNA interference, and viral infection in vitro, as well as animal models; clarify the upstream and downstream regulative mechanism related to its biological function by using molecular biology, cell biology combined with knockout mice model. This study will offer important theoretical significance and clinical value in screening molecular markers for prognosis and targeted therapy.

本组前期发现多量长链非编码RNA（lncRNA）在胃癌（GC）组织中差异表达。其中显著下调的TUSC7与GC患者多项临床病理学参数相关，且TUSC7相对低表达患者预后不良，过表达TUSC7可显著抑制胃癌细胞增殖、裸鼠皮下成瘤能力，但其在胃癌中具体生物学功能有待深入研究。生物信息学分析结合生物学实验，我们发现p53可在转录水平调控TUSC7表达；也初步确立了TUSC7的潜在靶分子，需验证具体调控机制。拟通过①调控TUSC7在体外细胞、活体动物的表达水平研究其在GC中的生物学功能；②应用分子生物学、细胞生物学实验和基因敲除小鼠模型等作为主要研究手段，阐明TUSC7调控胃癌发生发展的上下游调控机制，揭示p53-TUSC7-靶分子调节通路参与胃癌发生和恶性转归的生物学过程；③探索相关分子的临床病理相关性和预后预测意义。本项目对于筛选可用于预后评估及靶向治疗的分子标记物具有重要的理论意义和临床价值。

项目的背景：.本组前期发现多量长链非编码RNA（lncRNA）在胃癌（GC）组织中差异表达。其中显著下调的TUSC7与GC患者多项临床病理学参数相关，且TUSC7相对低表达患者预后不良，过表达TUSC7可显著抑制胃癌细胞增殖、裸鼠皮下成瘤能力，但其在胃癌中具体生物学功能有待深入研究。生物信息学分析结合生物学实验，我们发现p53可在转录水平调控TUSC7表达；也初步确立了TUSC7的潜在靶分子，需验证具体调控机制。.主要研究内容：拟通过①调控TUSC7在体外细胞、活体动物的表达水平研究其在GC中的生物学功能；②应用分子生物学、细胞生物学实验等作为主要研究手段，阐明TUSC7调控胃癌发生发展的上下游调控机制，揭示p53-TUSC7-靶分子调节通路参与胃癌发生和恶性转归的生物学过程；③探索相关分子的临床病理相关性和预后预测意义。.研究工作主要成果：.1. TUSC7可显著抑制胃癌细胞的增殖、裸鼠皮下成瘤能力。.2. TUSC7是一个野生型p53调控的基因。.3. TUSC7可影响多种miRNAs的表达水平。.4. TUSC7通过调控miR-23的表达水平影响胃癌细胞增殖。.5. TUSC7相对表达水平与GC患者组织学分级、浸润深度、神经侵犯等多项临床病理学参数相关，TUSC7相对低表达的患者预后不良。.科学意义：本项目对于筛选可用于预后评估及靶向治疗的分子标记物具有重要的理论意义和临床价值。