LncRNA PRR11-AS1通过PRR11及p53通路调控细胞增殖与凋亡影响肺腺癌预后的分子机制研究

Lung cancer is the most common malignant tumor in China, in which lung adenocarcinoma accounts for about 50% lung cancer in total. The prognostic mechanism affecting it has not been fully elucidated. A variety of long non-coding RNAs (lncRNAs) have been found to be associated with lung adenocarcinoma survival. We found that lncRNA PRR11-AS1 is associated with lung adenocarcinoma patient’s survival by bioinformatics data mining. By measuring lncRNA PRR11-AS1 expression in clinical samples, we confirmed that the high expression of lncRNA PRR11-AS1 in lung adenocarcinoma tissue. The overexpression of lncRNA PRR11-AS1 could promote lung adenocarcinoma cell proliferation and inhibit cell apoptosis. Further experiments showed that overexpression of lncRNA PRR11-AS1 could decrease the expressions of p53 downstream target genes including Noxa, Bax, Puma and p21. We propose the following hypothesis: "lncRNA PRR11-AS1 can regulate p53 pathway, affecting the proliferation and apoptosis of lung adenocarcinoma cells, and can participate in the prognostic process of lung adenocarcinoma". On the basis of pre-experiment, this project intends to understand the molecular mechanisms that how lncRNA PRR11-AS1 regulates lung adenocarcinoma cells by cell transfection, co-immunoprecipitation, and other experimental methods, which provides new molecular targets for the treatment of lung adenocarcinoma.

肺癌是我国最常见的恶性肿瘤，肺腺癌约占肺癌总数的一半，影响其预后机制尚未完全阐明。已有多种长链非编码RNA（lncRNA）被发现与肺腺癌预后存在相关性。本课题组通过生物信息学挖掘，发现肺腺癌患者癌组织中lncRNA PRR11-AS1与生存密切相关，其后在临床样本中证实lncRNA-PRR11-AS1在肺腺癌组织中高表达，转染lncRNA-PRR11-AS1慢病毒表达载体可以促进肺腺癌细胞的增殖同时抑制细胞凋亡，使p53通路相关蛋白Noxa、Bax、Puma及p21的表达显著下调。因此，我们提出假说“lncRNA-PRR11-AS1可以调控p53通路，影响肺腺癌细胞增殖与凋亡，参与预后过程”。在预实验的基础上，本课题拟在细胞模型中通过细胞转染、免疫沉淀技术等实验方法，深入探讨其在肺腺癌预后进程中的作用及相关分子机制，为肺腺癌的治疗寻找新的分子靶点。

肺腺癌占肺癌的比例约为35%-40%，了解影响其预后的因素是延长患者生存的重要研究方向。随着生物信息学的成熟，越来越多的长非编码链RNA被发现与肿瘤预后相关。我们前期生物信息学分析发现新型长非编码链RNA PRR11-AS1与肺腺癌的预后相关。为了进一步明确该长非编码链RNA发挥的生物学作用，我们通过整合多个开源数据库的分析，包括GEPIA2、UALCAN、CCLE、cBioportal、MEXPRESS、Metascape等，研究了PRR11和PRR11-AS1表达谱、甲基化调控、免疫浸润、癌症细胞干细胞、对生物功能的影响。我们进一步发现PRR11基因表达与临床指标、预后影响和潜在药物之间的相关性。. 本项目结果提示，PRR11-AS1在泛癌水平存在异常表达情况。PRR11的异常表达可能受到基因突变或甲基化的影响。PRR11可影响许多生物学机制，包括细胞周期、铁蛋白脱失、RNA m6A甲基化修饰、自噬。在转化医学意义上，PRR11的异常表达与LUAD的多个临床评估者相关。值得注意的是，PRR11表达对LUAD预后的影响也在独立数据库和荟萃分析中得到验证。. 在项目执行期间，发表了高水平学术论文5篇，其中SCI收录5篇；培养了博士研究生2名。本课题研究结果提示了新型长非编码链RNA PRR11-AS1在肺癌预后中发挥多种潜在影响，为进一步研究该分子如何参与肺癌侵袭、转移的分子机制和挖掘长非编码链RNA预后标志物研究提供数据基础。