长链非编码RNA MALAT1基因突变调控食管癌侵袭转移机理的研究

Several recent GWAS studies indicate that MALAT1, a long noncoding RNA, is recurrently mutated in different cancers. According to our preliminary sequencing data, MALAT1 is mutated in 9.8%（5/51） esophageal carcinoma (ESCC) specimen. Of note, the insertion of DNA sequence into the gene locus of MALAT1 chr11: 65501848 causes a significant enhancement of esophageal carcinoma migration. However, the impacts of MALAT1 mutation toward ESCC development are not clear. Thus, in this project, we will integrate different technologies, such as CRISPR, Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation and super resolution structure illumination system to draw a comprehensive mapping of interaction sites between MALAT1 and its protein partners, which is essential for uncovering the impacts of MALAT1 mutation. The dynamics and distribution of MALAT1 will also be analyzed. The relevant results provide insights into the biological consequences of MALAT1 mutation on ESCC metastasis and invasion.

近期全基因组关联研究表明长链非编码RNA MALAT1在多种癌症中高频突变。本项目前期通过对51例食管癌组织样本测序发现9.8%（5/51）患者样本中存在MALAT1基因突变， MALAT1基因座位chr11: 65501848插入突变显著增强食管癌细胞的迁移能力。然而，MALAT1基因突变如何影响食管癌侵袭转移尚不明确。基于此，本项目拟有机整合CRISPR技术、光活性增强的核糖核苷交联-免疫共沉淀技术和超分辨率结构光照明技术，解析MALAT1基因突变对MALAT1动态分布及MALAT1与蛋白质和染色质相互作用的影响，相关结果为阐明MALAT1基因突变促进食管癌侵袭转移提供理论依据。

MALAT1为一种长链非编码RNA（long noncoding RNA，lncRNA），其长度约为8kb，在脊柱动物中高度保守。全基因组关联研究表明MALAT1在多种癌症中高频突变；近期研究也表明MALAT1上在一段长度约1.5kb的区域内。本项目前期工作通过对食管癌组织样本测序发现9.8%的患者样本中存在MALAT1基因突变，其中MALAT1在上述富含m6A区域的扩增突变显著促进食管癌细胞的迁移能力。然而，MALAT1基因突变如何影响食管癌发生发展尚不明确。基于此，本项目高分辨率解析MALAT1与不同蛋白质相互作用位点，证明MALAT1能够与YTHDC1互作，该互作能够改变细胞核内核斑的组分，特异性缺失MALAT1的m6A修饰后对极大削弱了细胞的增殖和侵袭转移能力，该项目的研究揭示MALAT1表观修饰的生物学功能，相关结果对阐明MALAT1的基因突变及其m6A修饰如何影响食管癌侵袭转移提供理论依据。

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