TAZ调控microRNA-31-3p/CA2介导肝细胞肝癌侵袭转移的机制研究

The recurrence and metastasis of hepatocellular carcinoma (HCC) are the most important factors which influence on the prognosis of HCC patients and the treatment of HCC is still a tough problem. We have proved that TAZ could regulate the recurrence and metastasis of HCC, however, the mechanism is basically unknown. Our previous studies found that miR-31-3p expression was decreased after TAZ knock-down. Furthermore, miR-31-3p is over-expressed in clinic HCC tissue, and miR-31-3p expression was positively correlated to the TAZ expression. We further examined the effects of miR-31-3p on HCC growth and pulmonary metastasis by establishing an orthotopic liver tumor model in nude mice. MiR-31-3p knockdown resulted in significant decrease of tumor size, the number of pulmonary metastatic foci and decreased average size of pulmonary metastatic lesions. Based on these previous researches, we speculate that TAZ-induced miR-31-3p expression promote HCC invasion and metastasis. To test this hypothesis, we plan to investigate the relationship between TAZ and miR-31-3p and the prognostic value of miR-31-3p in more collected clinical samples. Next, we plan to investigate if the over-expression or knock-down of TAZ have an effect on the expression of miR-31-3p in vitro and vivo. Further to confirm that miR-31-3p is involved in HCC invasion and metastasis, Locked Nucleic Acid technical methods will be used. Finally, we should study if miR-31-3p induced invasion and metastasis by regulating its downstream target gene CA2 (carbonic anhydrase 2). This study will attempt to illuminate the molecular mechanism of TAZ in HCC invasion and metastasis and to establish the TAZ/miR-31-3p/CA2 signaling pathway which should supply some new therapeutic strategies and treatment targets in prevention of HCC invasion and metastasis.

肝癌转移复发是影响肝癌预后的重要因素和难题。TAZ对肝癌的转移复发有重要作用，但具体机制不明确，探索其信号通路和干预靶点可为预防肝癌复发转移提供新思路。前期研究发现：TAZ敲低后肝癌细胞株的miR-31-3p表达下降；在肝癌组织中，miR-31-3p表达升高,与TAZ表达正相关；miR-31-3p低表达的裸鼠原位肝癌移植模型发现肿瘤的生长速度减慢且肺部的转移结节变少变小。因此，我们推测TAZ调控miR-31-3p介导肝癌远处转移。本项目拟在此基础上，从大样本肝癌临床组织分析TAZ与miR-31-3p相关性和预后判断价值；构建TAZ过表达/敲低的体内体外模型，证实TAZ调控miR-31-3p表达；应用锁核苷酸技术，观察miR-31-3p在肝癌侵袭转移过程中的作用，同时探讨其是否通过调控靶基因CA2介导肝癌侵袭转移。本项目将阐明TAZ/miR-31-3p/CA2调控肝癌侵袭转移的分子机制。

肝癌转移复发是影响肝癌预后的重要因素和难题。TAZ对肝癌的转移复发有重要作用，但具体机制不明确，探索其信号通路和干预靶点可为预防肝癌复发转移提供新思路。该研究发现：1. 通过收集临床肝癌组织样本，我们发现miR-31-3p表达升高,与TAZ表达正相关；并且miR-31-3p与肝癌患者的临床预后有相关性；miR-31-3p低表达的裸鼠原位肝癌移植模型发现肿瘤的生长速度减慢且肺部的转移结节变少变小。通过细胞学和动物学实验，我们已经证明TAZ可以通过调控miR-31-3p/CA2信号通路介导肝癌远处转移，但该部分数据我们还在进一步整理，目前尚未发表文章；2. 通过TAZ的基因芯片检测，我们目前发现两个新的分子标记物ZSCAN31与CDV3，可能在肝癌中发挥着重要作用，该分子均与TAZ从蛋白结构上相互结合，与肝癌患者的临床预后有明确的相关性，目前该部分数据已经发表。通过该项目的实施及目前获得的相关数据，明确了肝癌复发转移的新的分子机制，为寻找肝癌复发转移的标志物和有效的干预靶点提供了新的方向。

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