组蛋白H3K9甲基化调控者miR-29家族在非小细胞肺癌发生发展中的作用及分子机制的研究

Lung cancer is a malignant tumor with high fatality rate, and causes great harm to human economic life. However, the mechanisms underlying the development of lung cancer reminds largely unknown. As the major histological class of lung cancer, NSCLC has always been diagnosed at a late stage, and the patients have poor prognosis after operation. With the rapid development of epigenetics study in the last decade, the understanding of the pathogenesis of lung cancer and the development of personalized lung cancer treatment are picking up pace. Previews studies showed that miR-29 (miR-29a，-29b and -29c) were downregulated in NSCLC, but their biological roles in lung cancer development reminds largely unknown were not fully elucidate. This research found that the H3K9 methyltransferases SETDB1 and Suv39h1 were the downstream target of miR-29, indicating that miR-29 might act as a regulator of H3K9 methylation in the development of NSCLC. Meanwhile, this research proposed to verify the two feedback loops of miR-29/SETDB1/C-MYC and miR-29/SETDB1/TP53 in NSCLC, so as to partially explain the underlying mechanism of miR-29 low expression in NSCLC.

肺癌是一种高致死率的恶性肿瘤，对人类的经济生活造成极大的危害，但其发生的具体机制尚未完全阐述。作为肺癌的主要组织类型，非小细胞肺癌(Non-Small Cell Lung Cancer, NSCLC）因其确诊晚及预后差等特点尤其受到关注。近十年来表观遗传学研究的快速发展为研究肺癌的发生发展以及开发肺癌个性化治疗方案提供了新思路。前期研究报道miR-29（miR-29a， -29b和-29c）在NSCLC中是低表达的，但其生物学功能仍未完全阐明。本课题发现组蛋白H3K9甲基化调控者SETDB1和Suv39h1是miR-29下游共同的靶基因，暗示miR-29有可能作为H3K9甲基化的调控者参与NSCLC的发生发展。同时通过实验验证NSCLC中miR-29/SETDB1/C-MYC和miR-29/SETDB1/TP53这两个反馈调控通路，以期解释miR-29在NSCLC中低表达的潜在机制。

肺癌是一种恶性肿瘤，死亡率高，对人类经济生活造成极大危害。非小细胞肺癌（NSCLC）是最常见的肺癌类型。随着近十年来表观遗传学研究的迅速发展，对肺癌发病机制的认识和肺癌个体化治疗的发展正在加快进行着。以前的研究表明，miR-29家族成员（miR-29s; miR-29a，-29b和-29c）在大多数人类癌症（包括NSCLC）中下调，但它们在肿瘤发生中的生物学作用及其调节机制仍未完全阐明。在这里，我们报道miR-29a，-29b和-29c在NSCLC中同时下调，并且组蛋白H3K9甲基转移酶SETDB1直接被miR-29靶向调控。此外，SETDB1对TP53进行负调控，且过表达SETDB1能下调miR-29s的表达水平，而TP53 对miR-29s进行正调节，且过表达TP53能下调SETDB1的表达水平。另一方面，作为TP53的下游靶标，H3K9甲基转移酶Suv39h1也被miR-29s通过TP53间接调控。改变miR-29s的表达变化后，进一步检测H3K9甲基化状态表明miR-29s能反向调控NSCLC中组蛋白H3K9上二甲基和三甲基化的修饰水平。综合来讲，我们的研究结果揭示了TP53 / miR-29s / SETDB1的反馈调节通路，并发现miR-29s是组蛋白H3K9甲基化的一个调控者，它们可能作为治疗NSCLC的潜在治疗靶点。