长链非编码RNA MIR22HG在肝癌发生发展中的作用及其机制研究

We have demonstrated that the expression of long noncoding RNAs (lncRNA) has been dysregulated in hepatocellular carcinoma (HCC) and may serve as novel prognostic markers and therapeutic targets (Gastroenterology, 2015. Oncogene, 2017.). Recently, our preliminary data showed that lncRNA MIR22HG was lowly expressed in HCC tissues compared with controls and its low expression was associated with portal vein tumor thrombus, tumor stage, and shorter survival of HCC patients. MIR22HG directly interacted with HuR and Ectopic expression of MIR22HG in HCC cells decreased the expression of cytoplasmic HuR and the downstream molecular of HuR. Thus, based on our data, we will investigate the roles and mechanisms of MIR22HG in the initiation and progression of HCC. Firstly, we will investigate the functions of MIR22HG by in vitro tumor assays, in vivo tumor assays, and MIR22HG knockout mice. Secondly, we will explore how MIR22HG generate the miR-22, and how ceRNA network involving MIR22HG/HuR/mRNA promote tumor progression. We also explore secondary structure of MIR22HG and provide a framework for understanding the functional properties of this important target. Lastly, the effects of MIR22HG and its related molecules will be identified by clinical multicenter samples in HCC. In conclusion, lowly expression of MIR22HG may act as a biomarker for poor prognosis in HCC and confer a malignant phenotype to tumor cells. This study may contribute to a better understanding of liver carcinogenesis and tumor progression.

我们前期研究发现长链非编码RNA（lncRNA）在肝癌发生、发展过程中发挥重要的调控作用（Gastroenterology, 2015. Oncogene, 2017.）。近期，我们预实验结果表明：lncRNA MIR22HG在肝癌中表达下调，其可与HuR直接结合，过表达MIR22HG下调细胞浆HuR的表达，同时也下调HuR调控的癌基因的表达。基于前期研究结果，我们拟深入探讨MIR22HG在肝癌发生发展中的作用及其机制。首先通过肿瘤体内外实验和MIR22HG基因敲除鼠探讨MIR22HG的生物学功能；其次，探讨MIR22HG与miR-22的关系，MIR22HG/HuR/癌基因之间互为调控的网络关系，并探讨MIR22HG二级结构对其功能和作用方式的影响；最后，利用肝癌多中心大样本探讨MIR22HG及其相互作用分子在肝癌中表达的临床意义。据此，阐明MIR22HG在肝癌中确切的生物学功能及机制。

我们前期研究发现长链非编码RNA（lncRNA）在肝癌发生、发展过程中发挥重要的调控作用（Gastroenterology, 2015. Oncogene, 2017.）。我们基于lncRNA MIR22HG在肝癌中表达下调，其可与HuR直接结合，过表达MIR22HG下调细胞浆HuR的表达，同时也下调HuR调控的癌基因的表达等研究结果，通过肿瘤体内外实验和MIR22HG基因敲除鼠、肝癌多中心大样本，探讨了MIR22HG的生物学功能、MIR22HG与miR-22的关系、MIR22HG二级结构对其功能和作用方式的影响、MIR22HG及其相互作用分子在肝癌中表达的临床意义。本研究主要研究成果为 MIR22HG 的低表达与肿瘤的进展有关，并且 MIR22HG 的表达代表了 HCC 患者预后的独立预测因子。在功能上，MIR22HG 过表达抑制了肿瘤细胞的增殖、迁移、侵袭和转移。在肝癌细胞中，MIR22HG 和 miR-22-3p 通过抑制 HMGB1 而抑制迁移和侵袭。此外，miR-22-3p 抑制或 HMGB1 过表达可逆转 MIR22HG 对上述过程的抑制作用。这些数据表明，MIR22HG 和 miR-22-3p 是共表达的，并且在功能上是协调的。HUR 介导了肿瘤抑制基因 MIR22HG 的稳定，从而破坏了许多癌基因的稳定。MIR22HG 通过衍生 miR-22-3和竞争性结合 HUR 抑制肝癌细胞的增殖、侵袭和转移，导致多癌基因下调和 HMGB1 信号失活。本研究还发现 MIR22HG 可以调节 HUR 的亚细胞定位，野生型或突变型 MIR22HG 的过表达促进了 HUR 从细胞质向细胞核的转位。我们的发现支持了解 lncRNA 模块在肝癌中的关键作用将可能导致识别治疗肝癌的新的治疗靶点。