AMPK调控的新lncRNA MITA1在肿瘤中的功能及其分子机制研究

Long noncoding RNAs (lncRNAs) play critical roles in various human diseases, especially cancer. Thus far, only a few lncRNAs have been shown to be associated with the development of cancer. By high throughput RNA sequencing, we identified a novel lncRNA named metabolic stress-induced tumor activator 1 (MITA1). Our pilot experiments showed that MITA1 can be induced by multiple metabolic stresses, and this induction depends on AMPK. Moreover, MITA1 knockdown has no role in cancer cell growth, but significantly inhibit cancer cell migration and invasion. Additionally, MITA1 is remarkably increased in clinical cancer samples. Based on these preliminary data, we speculated that AMPK-regulating MITA1 may act as a driver for tumor metastasis. To test this hypothesis, this project will be carried out as follows: First, we will try to elucidate the mechanism underlying the effects of AMPK on MITA1 expression under metabolic stresses. Second, we will determine the role of MITA1 in tumor growth and metastasis. Third, by identifying MITA1 targets through high throughput technologies, we will try to reveal the mechanism that MITA1 promotes metastasis. Fourth, we will strengthen the link between AMPK-MITA1-target regulatory pathway and tumor development by examining their expression in clinical tumor samples. Taken together, the project will uncover a regulatory network that a novel lncRNA coupling metabolic pathways promotes metastasis, which will provide new targets and strategies for the diagnosis and treatment of human cancers.

长非编码RNA与肿瘤发生发展密切相关。目前只有少数长非编码RNA在肿瘤中的功能和作用机制被阐明。利用转录组测序，我们发现了一个全新长非编码RNA MITA1，预实验结果提示：葡萄糖饥饿等代谢应激诱导MITA1表达；AMPK可能介导代谢应激对MITA1的诱导作用；抑制MITA1显著阻碍肿瘤细胞的迁移和侵袭；MITA1在临床肿瘤样本中显著高表达。由此我们推测：代谢应激-AMPK调控的MITA1促进肿瘤发生发展。为证实此设想，拟开展如下研究：1）明确代谢应激及AMPK对MITA1的调控作用及机制；2）揭示MITA1在肿瘤生长和转移中的功能；3）鉴定MITA1作用靶点，解析其调控肿瘤转移的机制；4）建立AMPK-MITA1-靶点通路与肿瘤的相关性。本项目有望揭示一个耦联代谢通路的全新长非编码RNA参与肿瘤转移的调控网络，为肿瘤诊断和治疗提供潜在的新靶点和新思路，具有重要的理论意义和临床价值。

癌症是（恶性肿瘤）是目前全世界主要死亡原因之一，而由于肿瘤的异质性、易转移等特点，很多癌症的治疗进展缓慢，亟待发现新的靶标分子和治疗手段。我国是癌症大国，肝癌、肺癌、胃癌等为主要高发癌症，尤其是肝癌为我国的特色癌，发病人数已占到全球患者的一半，是医学界亟需攻克的一大癌肿。.长非编码RNA（long non coding RNA, lncRNA）是一类长度大于200 nt的非编码RNA。lncRNA与各种因子交互作用，形成复杂的调控网络，在许多基本生命过程和人类疾病中发挥着重要作用，尤其是与癌症密切相关。目前只有少数长非编码RNA在肿瘤中的功能和作用机制被阐明。LncRNA数量庞大，表达丰度低，且组织特异性强，可以预见大量癌症相关的lncRNAs亟待发现和探究。因此本项目旨在发现和探究新的lncRNA分子在肿瘤发生发展过程的功能和分子机制研究。.本项目通过转录组测序发现了一个全新长非编码RNA MITA1。进一步研究发现，多种类型肿瘤细胞中，葡萄糖饥饿等代谢应激诱导MITA1表达；可能甲基化依赖的AMPK通路介导代谢应激对MITA1的诱导作用；在细胞水平上，抑制MITA1显著阻碍肿瘤细胞的迁移和侵袭；MITA1在临床肿瘤样本中显著高表达；初步动物实验表明，抑制MITA1也能阻碍体内肿瘤细胞转移。综上，本研究发现并鉴定了全新lncRNA MITA1在肝癌转移中的重要功能及其作用机制，建立了能量应激与肿瘤转移的新联系，并初步揭示MITA1的作用机制，为后续深入解析MITA1在癌症中的调控网络奠定基础，为肝癌提供新的诊断标志物和独特的干预靶点，具有重要的理论意义和现实价值。