长链非编码RNA MOTALA在肺腺癌发生发展中的作用和机制研究

The important role of long non-coding RNA (lncRNA) in tumorigenesis and development has gained increasingly more attention in recent years, but the studies on lncRNA in lung cancer are very rare. By using lncRNA microarray and bioinformatics analysis, we screened a key lncRNA-MOTALA which was found important for gene different expression between lung adenocarcinoma and normal tissues. MOTALA is located on the exon of MUC5B gene. MOTALA expression is up regulated in lung adenocarcinoma tissues and significantly associated with pathological stages. Based on the previous evidence, bioinformatics analysis and our pilot results, we hypothesize that the lncRNA transcribed by MOTALA could combined with some kind of target proteins, then regulate MUC5B or other cancer-related genes expression, and thus participate in the development and progression of lung adenocarcinoma. To verify this hypothesis, this project is designed to study the role of MOTALA in lung cancer from different perspectives, i.e. clinical study, molecule, cell and animal studies. Our aims are to further clarify the relationship of MOTALA expression with clinical features of lung cancer; to explore the effect of MOTALA on biological behavior of lung adenocarcinoma cells and its potential mechanisms; to analyze target protein molecules combining with MOTALA and their biological significance. This project will provide a new theoretical basis for further understanding of the role and mechanism of lncRNA in lung cancer pathogenesis.

长链非编码RNA（lncRNA）在肿瘤发生发展中的重要性日趋受到重视，目前在肺癌中的研究还极少。我们通过lncRNA表达谱芯片和生物信息学分析，筛选到对肺腺癌和正常肺组织基因表达差异起重要作用的关键lncRNA- MOTALA。MOTALA位于MUC5B基因外显子中，预实验发现MOTALA在肺腺癌组织中表达上调，且与肿瘤的病理分期显著关联。结合文献、生物信息学分析和预实验结果，我们推测MOTALA转录后生成的lncRNA，可与某种靶蛋白结合，调控MUC5B或其他癌症相关基因的转录表达，从而参与肺腺癌的发生和发展。为验证上述假说，本项目拟从临床研究、分子、细胞、动物不同水平进一步明确MOTALA表达与肺腺癌临床特征的关系，探讨MOTALA对肺腺癌细胞生物学行为的影响及其机制，分析与MOTALA结合的靶蛋白分子及其生物学意义,为深入认识lncRNA在肺癌发病过程中的作用及机制提供新的理论依据。

肺癌仍是目前最普遍和最致命的癌症。肺癌发生和发展的分子机制仍不清楚。长链非编码RNA（lncRNA）在肿瘤发生发展中的重要性日趋受到重视，目前在肺癌中的作用仍有待研究。我们通过lncRNA表达谱芯片和生物信息学分析，筛选到对肺腺癌和正常肺组织基因表达差异起重要作用的关键lncRNA— MUC5B-AS1（MOTALA）。本项目主要从临床研究、分子、细胞、动物不同水平明确MUC5B-AS1表达与肺腺癌临床特征的关系，探讨MUC5B-AS1对肺腺癌细胞生物学行为的影响及其分子机制。结果发现MUC5B-AS1是一种新的MUC5B长非编码反义转录物。与正常肺组织相比，肺腺癌组织中MUC5B-AS1表达上调。此外，MUC5B-AS1在体外促进肺癌细胞迁移和侵袭，在体内促进肺癌细胞转移。MUC5B-AS1及其母基因MUC5B在肺腺癌中高度共表达并相互调节。MUC5B的高表达与肺腺癌预后差显著相关。在机制上，MUC5B-AS1通过与MUC5B形成RNA-RNA保护性双链，增加肺腺癌中MUC5B的表达水平，进而促进细胞迁移和侵袭。研究结果提示MUC5B-AS1在肿瘤转移中作为致癌基因起重要作用，表明MUC5B-AS1可能是有潜力的治疗候选靶点之一。本研究为深入认识lncRNA在肺癌发病过程中的作用及机制提供了新的理论依据。