ADAR1在肝癌发生发展中的功能及机制研究

肝细胞癌（Hepatocellular carcinoma,HCC，后文简称为肝癌）作为最常见的恶性肿瘤之一，致死率在中国位居第二位仅次于肺癌。目前治疗早期肝癌较好的治疗方式为外科切除，肝脏移植及消融治疗。但由于肝癌起病隐匿，早期症状不明显，病人往往在中晚期才被确诊，只能通过化疗、靶向药物等手段进行治疗。又因其化疗响应率低，高复发，易转移，故治疗效果极差，一年生存率一般不超过12%。因此，深入探讨肝癌发生发展过程中的调控机制，寻找潜在的作用靶点具有必要性及迫切性。

 ADAR1（adenosine deaminase acting on RNA 1）作为腺苷脱氨酶ADAR家族成员，介导由腺嘌呤（A）至次黄嘌呤（I）的转化，可通过编辑内源性双链RNA进而抑制以MDA5为代表的干扰素通路激活。过往研究已发现，ADAR1在多种肿瘤中表达异常，然而ADAR1在肝癌中的具体功能和机制还有待进一步研究。通过对实验室拥有的临床样本以及TCGA等数据库中的临床数据进行的分析证明，ADAR1在肝癌中普遍高表达，且与病人不良预后相关。随后，体外模型实验证明ADAR1的敲低或敲除能降低肝癌细胞的生长与侵袭能力。基于过往研究中报道ADAR1功能与MDA5干扰素通路密切相关，本文构建了同时敲除ADAR1与MDA5的肝癌细胞系，结果显示ADAR1对生长的调控依赖MDA5干扰素通路，而ADAR1对细胞侵袭的调控具有独立于MDA5干扰素通路以外的功能和机制。为了进一步研究其调控机制，本文通过交叉对比ADAR1-p110过表达小鼠与肝癌细胞系的RNA-seq结果，从中筛选到TUBA1A基因（Tubulin α-1 A）。在数据库、临床样本及细胞系的验证中，TUBA1A的表达量在肝癌中普遍上调，与病人不良预后相关，并与ADAR1的表达量呈正相关性。在肝癌细胞系中，TUBA1A的敲低能降低细胞的生长与侵袭能力。综上所述，本文检测发现ADAR1在肝癌中普遍高表达，且与病人不良预后相关，ADAR1能够调控肝癌细胞的生长与侵袭，生长方面的功能依赖于MDA5通路，侵袭方面具有独立于MDA5通路的作用机制，且有可能通过调控TUBA1A表达来发挥作用。上述结果为靶向ADAR1治疗肝癌提供了可能的分子机制及理论依据。

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