非典型多聚腺苷酸聚合酶2介导的miR-125b3'端单腺苷酸化在HCC复发转移中的作用及机制研究

Dysregulation of microRNAs expression has been found to be associated with tumor progression. Several recent studies have found that post-transcriptional modification of miRNAs participate in the development of tumor. Previously, we found that PAPD2 regulated miR-125b 3' monoadenylation (miR-125b+A) in HCC. In addition, both PAPD2 and miR-125b+A were overexpression in tumor tissues. Moreover, 3' monoadenylation positively correlated with the invasion and metastasis potential of HCC and abolished repression ability of miR-125b in its target genes. Based on these results, we will first investigate the relationship of PAPD2 and miR-125b+A expression with clinicopathologic characteristics and prognosis of HCC. Then, the biological function and mechanism of miR-125b+A on HCC was analyzed by a group of experiments, like growth curves, in situ xenograft nude mouse model. Then, we plan to screen and identify the key downstream target of miR-125b+A by protein antibody array. Finally, with in situ xenograft nude mouse model, the value of miR-125b+A targeted therapy was evaluated. In conclusion, the present study will elucidate the biological function and molecular mechanism of PAPD2 mediated miR-125b 3' monoadenylation in regulating recurrence and metastasis of HCC, which could provide novel theoretical basis and experimental evidence, as well as potential novel target for the treatment of HCC.

miRNAs异常表达与肿瘤进展相关，研究证实miRNAs转录后修饰参与上述过程。我们前期发现HCC中PAPD2介导miR-125b发生3'端单腺苷酸化(miR-125b+A)，并且癌组织中PAPD2和miR-125b+A表达均上调，3'端单腺苷酸化促进HCC侵袭转移，并改变了miR-125b调控靶基因的能力。本项目拟在前期研究基础上，首先分析PAPD2和miR-125b 3'端单腺苷酸化与HCC患者临床病理特征和预后的关系；然后利用慢病毒技术，通过生长曲线、裸鼠原位成瘤等一系列实验研究miR-125b+A在肝癌复发转移中的作用及机制，并利用蛋白芯片等技术筛选鉴定其下游靶基因；利用动物模型探讨靶向miR-125b+A在肝癌治疗中的价值。本研究旨在阐明PAPD2介导的miR-125b 3'端单腺苷酸化在肝癌复发转移中的作用及分子机制，为临床预防、治疗HCC复发转移提供新的研究思路和实验基础。