非小细胞肺癌功能性lncRNA鉴定与生物学机制研究

Long non-coding RNAs (lncRNAs) play significant roles in the development, progression and metastasis in human cancers. However, in the field of Non-Small Cell Lung Cancer (NSCLC), clinically relevant lncRNAs may remain elusive: on the one hand, NSCLC-related lncRNA have yet to be discovered; on the other hand, for the majority of lncRNAs found to be related to NSCLC, the underlying biological function and mechanism are still not clear..According to the latest researches, several applicable and measurable features of functional lncRNAs are valuable in prioritizing candidates for further functional examination and in guiding the design of experiments. Approaches utilizing each of these features can extract potential candidates for characterization from an initial pool of lncRNAs. However, isolated use produces insufficient evidence to generate detailed hypotheses of function. We proposed that integrative approaches that test separate avenues of lncRNA functionality can produce a more refined candidate list, with some insight as to how they are exerting their function. In this study, we applied transcriptome sequencing(RNA-seq) to 101 NSCLC tumor biopsies and their matched normal tissues. We will apply integrative computational approaches to prioritizing functional lncRNAs, and exploring their potential biological function and molecular mechanism, which would narrow the functional search space for experiments. And then we will use multiple cell and molecular biology experiments to validate the function and mechanism of 1 or 2 candidate lncRNAs in NSCLC. .This study is designed to provide a comprehensive list of the functional lncRNAs in NSCLC and its putative molecular mechanism, which will provide potential molecular markers and targets for early clinical diagnosis and treatment of NSCLC.

长非编码RNA（lncRNA）在癌症的发生、发展和转移中发挥重要作用。迄今为止，在非小细胞肺癌（NSCLC）研究领域中，对lncRNA的研究仍处于初级阶段：一方面，与NSCLC相关的lncRNA还有待发掘；另一方面，对于大多数已鉴定到的lncRNA，其作用机制尚不明确。基于最新研究和我们的预分析结果，我们认为对lncRNA多层面特征进行整合分析有助于高效地从高通量数据中挖掘出影响肺癌发生发展的功能性lncRNA。本课题拟通过对NSCLC全基因组范围内的lncRNA进行生物信息学整合分析，全面筛选出NSCLC功能性lncRNA，并提供功能和机制注释，最后结合实验生物学验证，深入探索lncRNA在NSCLC恶性发展过程中的生物学功能和分子机制。本研究的开展，有助于全面了解NSCLC恶性发展中的功能性lncRNA及其作用机制，为临床早期诊断和治疗提供潜在的分子标志物和靶点。

肺癌是全球范围内发病率和死亡率增长最快，对人类健康和生命威胁最大的恶性肿瘤之一，也是我国综合发病率和死亡率最高的癌症，其中非小细胞肺癌（NSCLC）约占所有肺癌的80%。非编码RNA在包括NSCLC在内的各种肿瘤的发生、发展和转移中发挥重要作用。本课题利用生物信息学方法对NSCLC全基因组范围内的长非编码RNA（lncRNA）进行表观遗传修饰、保守性和共表达等多维度特征的整合分析，筛选出了一系列筛选功能性的lncRNA，并根据整合分析结果对其作用机制进行了预估,包括通过位置保守与转录因子互作、通过antisense方式调控sense基因等。通过实验我们验证了一个lncRNA DDX11-AS1在肺癌细胞增殖和迁移中的作用。NSCLC的两个主要亚型肺鳞癌（LUSC）和肺腺癌（LUAD）在生物学特征、分子表型和治疗策略上都存在显著差别。本研究还从lncRNA的角度揭示了LUAD与LUSC之间的差异，并为进一步的实验验证LUAD和LUSC间不同的分子标志物和LUAD与LUSC的区别治疗提供了新的线索。本研究的开展，有助于全面了解NSCLC恶性发展中的功能性非编码RNA及其作用机制，为临床早期诊断和治疗提供潜在的分子标志物和靶点。