RBM8A在肝细胞癌中通过EMT调节奥沙利铂耐药的研究

奥沙利铂耐药是肝癌治疗中亟待解决的难题。上皮-间充质转化（EMT）已被证实与奥沙利铂耐药密切相关。我们前期研究发现：RBM8A在肝癌组织中高表达，并且可诱导体外细胞株的 EMT。RBM8A是一种RNA结合基序蛋白，主要调控对异常mRNA的清除，并广泛参与肿瘤发展，但能否通过所诱导的EMT参与奥沙利铂耐药尚不清楚。本研究拟：1)构建RBM8A沉默及过表达的人肝癌细胞模型，建立相应的奥沙利铂耐药株。2)评价各细胞株的肿瘤相关功能、耐药性、EMT特征，基因芯片筛选差异表达基因并进行下游验证。3)动物实验研究RBM8A通过EMT调节奥沙利铂耐药的作用。4)临床随访分析RBM8A的表达水平与接受奥沙利铂化疗患者疗效的相关性。本研究将阐明RBM8A与肝癌奥沙利铂耐药的潜在关系，有望为逆转肝癌耐药提供新的理论依据及潜在治疗靶点。

Oxaliplatin(OXA) resistance is urgently needed to be solved in the treatment of hepatocellular carcinoma (HCC). It was found that OXA resistance is associated with epithelial-mesenchymal transition (EMT).Our previous work demonstrated that RBM8A was highly expressed in HCC primary tumors and induced EMT in HCC cell lines. RBM8A (RNA-binding motif protein 8A),as a RNA-binding protein, mainly regulates the clearance of abnormal mRNA and widely participates in tumor progression. However, it still remains unknown that whether the EMT driven by RBM8A plays a role in the development of OXA resistance. The present study aims to: (1) Establish OXA-resistant RBM8A-silencing or RBM8A-overexpressing human HCC cell lines. (2) Evaluate the cancer cell biological functions, drug resistance and EMT characteristics in the HCC cell lines; screen out and testify the differentially-expressed gene by gene microarrays and further determine the downstream pathways. (3) Clarify the mechanism of RBM8A-regulated OXA resistance via EMT in HCC in animal model. (4) Follow-up study is carried out to investigate the correlation of RBM8A expression level with the clinical effect of HCC patients receiving OXA. Our study is going to clarify the potential relationship between RBM8A and OXA resistance in HCC and may offer novel theoretical proofs and potential target for the reversal of drug resistance.