H3K27乙酰化调控的lncRNA SFTA1P调节TGFBR2表达并维持RNA聚合酶Ⅱ活性从而抑制肺腺癌发生发展的作用和机制研究

The role and mechanism of lncRNA in lung cancer are far from clarified. We found that a new lncRNA SFTA1P was down regulated in lung adenocarcinoma, and its low expression was significantly correlated with the poor prognosis of lung adenocarcinoma. Overexpression of SFTA1P inhibited the proliferation and migration of lung adenocarcinoma cells. The function and mechanism of lncRNA are closely related to its subcellular localization. We found that SFTA1P exists in both cytoplasm and nucleus of lung adenocarcinoma cells. According to a large number of pre experiments, bioinformatics analysis and the existing research evidence, we deduced the following hypothesis: SFTA1P in the cytoplasm could bind to miR-665 as a ceRNA, relieve the inhibition of miR-665 on TGFRB2 and upregulate the expression of TGFRB2, and thus regulate TGF- beta /Smad signaling pathway; SFTA1P in the nucleus could increase the free state of P-TEFb protein by combining CCNT1, and maintain RNA polymerase II activity, thereby inhibit the occurrence and development of lung cancer. In order to verify this hypothesis, we will carry out research from multiple levels of population, animal, cell and molecule to clarify the role and mechanism of SFTA1P in lung adenocarcinoma. Our research will help us to further understand the molecular basis of lung cancer and provide new ideas for the prevention and treatment of lung cancer.

LncRNA在肺癌中的作用和机制远未阐明。我们发现一个新的lncRNA SFTA1P在肺腺癌中显著下调，其低表达与较差的肺腺癌预后相关，过表达SFTA1P能抑制腺癌细胞增殖和迁移。LncRNA的功能和机制与其亚细胞定位密切相关，我们发现SFTA1P在肺腺癌细胞胞浆和胞核中均有存在。根据大量预实验、生物信息学分析和现有研究证据，我们推测：细胞浆中的SFTA1P作为ceRNA，竞争性结合miR-665，解除miR-665对TGFRB2表达的抑制，上调TGFRB2表达，进而调节TGF-β/Smad信号通路；细胞核中的SFTA1P通过结合CCNT1等蛋白，促进P-TEFb游离状态增多，进而维持RNA聚合酶Ⅱ活性，从而抑制肺腺癌发生发展。为验证此假说，本项目拟从人群、动物、细胞和分子多个层次开展研究，明确SFTA1P在肺腺癌发生发展中的作用和机制，有助于深入认识肺癌的分子基础，为肺癌防治提供新思路。

本研究鉴定了一种假基因衍生的长链非编码RNA SFTA1P，可被N6-甲基腺苷（m6A）修饰，且可以调控非小细胞肺癌（NSCLC）中两个主调节因子TGFBR2和P-TEFb的活性。SFTA1P在肺组织中特异性表达，在NSCLC组织中表达下调，且与不良预后呈负相关。功能研究发现SFTA1P在体外和体内抑制NSCLC的生长和转移。机制研究表明，SFTA1P位于细胞核和细胞质中，并在细胞的不同定位发挥不同的作用机制。在细胞质中，SFTA1P作为miR-665的ceRNA，上调TGFBR2。在细胞核中，SFTA1P与P-TEFb复合物结合，随后抑制RNA聚合酶II的转录酶活性。SFTA1P的不同细胞定位协调TGFBR2和P-TEFb发挥作用，m6A RNA修饰参与了SFTA1P的细胞定位。我们的发现揭示了SFTA1P在NSCLC中发挥抑癌作用，这可能为NSCLC治疗提供了新的理论依据。