miR-122在肝细胞中调节DNA损伤修复的机理研究

Dicer is an enzyme involved in the biogenesis of miRNAs, and miR-122 is a liver specific miRNA. Both of them can regulate hepatitis B virus (HBV) replication. Moreover, they are both downregulated in the liver tissues of chronic hepatitis B patients and HBV-related Hepatocellular Carcinoma (HCC). It has been demonstrated that knockout of Dicer or miR-122 leads to hepatocarcinogenesis. However, they exhibit completely different roles in DNA damage response. We have reported that Dicer ablation leads to DNA damage, but our preliminary data show that miR-122 overexpression inhibits DNA repair in HCC cells. In this study, we aim to elucidate the molecular mechanism underlying the role of miR-122 in DNA damage repair, and investigate the effect of miR-122 overexpression on DNA damage repair in Dicer-deficient hepatocytes and HCC cells. The study may help to understand the role of miR-122 and Dicer in hepatocarcinogenesis, and shed light on the treatment of HBV-related HCC.

Dicer是miRNA生物合成过程中的一个关键酶，miR-122是一个肝特异的miRNA，它们都能够调节乙型肝炎病毒（HBV）的复制。与正常肝组织相比， Dicer和miR-122在慢性乙型肝炎病人肝组织中表达降低；与癌旁组织相比，Dicer和miR-122在HBV相关肝癌组织中表达也降低。此外，在肝脏中敲除Dicer或miR-122都能导致肝癌发生。虽然如此，它们对DNA损伤修复的调节作用却截然相反。我们发现，抑制Dicer表达能诱导DNA损伤，但是在肝癌细胞中过表达miR-122却能抑制DNA损伤修复。本项目拟研究miR-122调节DNA损伤修复的机理，并探讨miR-122的过表达是否使Dicer缺失诱导的DNA损伤进一步恶化。本项目的开展有助于阐明miR-122及Dicer在慢性乙型肝炎恶性转化过程中的作用，可能为HBV相关肝癌的治疗提供新思路。

Dicer是miRNA生物合成过程中的一个关键酶，miR-122是一个肝特异的miRNA，在肝脏中敲除Dicer或miR-122能够诱发脂肪性肝炎和肝癌。我们发现Dicer和miR-122在慢性乙型肝炎向肝癌恶性转化过程中表达逐步降低；抑制Dicer表达能诱导DNA损伤，过表达miR-122却能抑制DNA损伤修复。本项目主要研究了miR-122调节DNA损伤修复的机理。我们发现Dicer和ALDOA是miR-122的两个靶基因，miR-122通过这两个靶基因调节DNA损伤修复。Dicer通过与SIRT7相互作用调节非同源末端连接介导的DNA损伤修复。ALDOA是糖酵解途径中的一个关键酶，我们发现ALDOA能够与DNA-PKcs结合，增强DNA-PK活性、促进DNA修复。在p53缺失的细胞中过表达ALDOA促进肿瘤生长。DNA损伤一方面通过诱导基因突变促进肿瘤发生，另一方面通过诱导天然免疫分子MICA/B和炎症因子的表达加重炎症促进肿瘤发生。DNA损伤还能诱导miR-134和miR-34a的表达，miR-134增强DNA修复效率、诱导肿瘤化疗耐受，miR-34a通过促进MICB的表达诱导免疫细胞介导的肝损伤。本研究结果可能为肝癌的防治提供理论基础。