School of Life Sciences, Zhengzhou University, Zhengzhou, China.
University of Chinese Academy of Sciences, Beijing, China.
J Clin Invest. 2021 Oct 1;131(19). doi: 10.1172/JCI148020.
Liver tumor-initiating cells (TICs) are involved in liver tumorigenesis, metastasis, drug resistance, and relapse, but the regulatory mechanisms of liver TICs are largely unknown. Here, we have identified a functional circular RNA, termed circRNA activating MAFF (cia-MAF), that is robustly expressed in liver cancer and liver TICs. cia-MAF-KO primary cells and cia-maf-KO liver tumors harbor decreased ratios of TICs, and display impaired liver tumorigenesis, self-renewal, and metastatic capacities. In contrast, cia-MAF overexpression drives liver TIC propagation, self-renewal, and metastasis. Mechanistically, cia-MAF binds to the MAFF promoter, recruits the TIP60 complex to the MAFF promoter, and finally promotes MAFF expression. Loss of cia-MAF function attenuates the combination between the TIP60 complex and the MAFF promoter. MAFF is highly expressed in liver tumors and liver TICs, and its antisense oligo (ASO) has therapeutic potential in treating liver cancer without MAFA/MAFG gene copy number alterations (CNAs). This study reveals an additional layer for liver TIC regulation as well as circRNA function, and provides an additional target for eliminating liver TICs, especially for liver tumors without MAFA/MAFG gene CNAs.
肝肿瘤起始细胞（TICs）参与肝肿瘤发生、转移、耐药和复发，但 TIC 的调控机制在很大程度上尚不清楚。在这里，我们鉴定了一种功能性环状 RNA，称为环状 RNA 激活 MAFF（cia-MAF），它在肝癌和肝 TICs 中强烈表达。cia-MAF-KO 原代细胞和 cia-maf-KO 肝肿瘤中 TIC 的比例降低，并且显示出肝肿瘤发生、自我更新和转移能力受损。相比之下，cia-MAF 的过表达可促进肝 TIC 的增殖、自我更新和转移。在机制上，cia-MAF 与 MAFF 启动子结合，募集 TIP60 复合物到 MAFF 启动子，并最终促进 MAFF 的表达。cia-MAF 功能的丧失会减弱 TIP60 复合物与 MAFF 启动子之间的结合。MAFF 在肝肿瘤和肝 TICs 中高表达，其反义寡核苷酸（ASO）在不改变 MAFA/MAFG 基因拷贝数的情况下具有治疗肝癌的潜力。这项研究揭示了肝 TIC 调控的另一个层面以及环状 RNA 的功能，并为消除肝 TIC 提供了另一个靶点，特别是对于没有 MAFA/MAFG 基因 CNAs 的肝肿瘤。
