SNRPB-GOLGA4可变剪接信号轴在肝癌发生发展中的功能和分子机制

Hepatocellular carcinoma(HCC) is one of the most common cancers in China，aberrant alternative splicing of pre-mRNA in liver cells will affect the function of key proteins and directly lead to the occurrence of HCC. However, HCC-associated alternative splicing and its regulatory mechanism are still poorly understood. By transcriptome sequencing of HCC tissues, we find that SNRPB the core component of spliceosome is highly expressed in HCC tissues, and its expression level is closely related to the prognosis of HCC patients. Further studies reveal that SNRPB has cancer promoting function and regulates the alternative splicing of exon 22 of GOLGA4 in HCC cell lines. Therefore, we infer that SNRPB regulates the interaction between GOLGA4 and Arl1-GTP by regulating the alternative splicing of exon 22 of GOLGA4, to achieve GOLGA4 Golgi localization and promote the occurrence and development of HCC. This project aims to use transcriptome sequencing, RNA binding protein immunoprecipitation, protein quantitative mass spectrometry and other techniques to study the function of SNRPB and its molecular mechanism of regulating GOLGA4 alternative splicing in HCC; to clarify the function and molecular mechanism of SNRPB-GOLGA4 alternative splicing signaling axis and its correlation with HCC patients’ prognosis; to provide potential targets for diagnosis and precise treatment of HCC.

肝癌是我国高发的癌症之一，肝细胞内前体mRNA异常可变剪接会影响关键蛋白的功能，直接导致肝癌发生，但肝癌相关的可变剪接及其调控机制知之甚少。通过对肝癌病人组织转录组测序，申请人发现剪接体核心成分SNRPB在肝癌中高表达，其表达量与肝癌病人预后密切相关，进一步研究发现SNRPB在肝癌细胞系中具有促癌功能并调控GOLGA4基因22号外显子的可变剪接。由此我们推测，SNRPB通过调节GOLGA4基因22号外显子的可变剪接来调节GOLGA4与Arl1-GTP的相互作用，实现GOLGA4的高尔基体定位，促进肝癌的发生发展。本项目拟利用转录组测序、RNA结合蛋白免疫沉淀、蛋白定量质谱等技术，研究SNRPB在肝癌内的功能及其调控GOLGA4可变剪接的分子机制，明确SNRPB-GOLGA4可变剪接信号轴的功能和分子机制及其与肝癌病人预后的相关性，为肝癌诊断和精准治疗提供潜在靶点。

肝癌是我国高发的癌症之一，肝细胞内前体mRNA异常可变剪接会影响关键蛋白的功能，直接导致肝癌发生，但异常可变剪接调控肝癌发生发展的机制尚不清楚。通过分析肝癌病人组织芯片检测结果，申请人发现剪接体核心成分SNRPB在肝癌中高表达，SNRPB表达量与肝癌病人预后密切相关，SNRPB促进肝癌细胞的增殖和迁移。进一步研究发现SNRPB在肝癌中主要通过调控可变剪接发挥功能，SNRPB促进TADA2A基因4号外显子的融合，产生全长变体TADA2A-L，其促进肝癌细胞的增殖和迁移。本项目利用转录组测序、RNA结合蛋白免疫沉淀、蛋白质谱等技术，研究SNRPB在肝癌内的功能及其调控TADA2A 4号外显子可变剪接的分子机制，明确SNRPB-TADA2A信号轴在肝癌中的功能及其与肝癌病人临床数据的相关性，为肝癌精准治疗和临床药物开发提供理论基础和实验依据。