Circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF
Zhenzhen Chen, … , Zusen Fan, Pingping Zhu
Zhenzhen Chen, … , Zusen Fan, Pingping Zhu
Published August 17, 2021
Citation Information: J Clin Invest. 2021;131(19):e148020. https://doi.org/10.1172/JCI148020.
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Research Article Cell biology Oncology

Circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF

Abstract

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.

Authors

Zhenzhen Chen, Tiankun Lu, Lan Huang, Zhiwei Wang, Zhongyi Yan, Yubo Guan, Wenjing Hu, Zusen Fan, Pingping Zhu

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Figure 2

cia-MAF knock out impairs liver TIC self-renewal.

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cia-MAF knock out impairs liver TIC self-renewal. (A) Real-time PCR (le...
(A) Real-time PCR (left) and Northern blot (right) analyses for cia-MAF knockout efficiency. circ KO, cia-MAF knock out. (B) CD44 FACS for TIC detection, using cia-MAF–KO and control cells. n = 3 independent samples for detection. (C) Sphere formation of cia-MAF–KO cells, with typical images in the left panels and sphere formation ratios in the right panel. Scale bars: 500 μm. (D) Tumor propagation of WT and cia-MAF–KO cells, which were subcutaneously injected into BALB/c nude mice. Tumor volumes were measured every 3 days. (E) Three months of tumor initiation assay using gradient numbers of cia-MAF–KO and control cells. n = 7 mice for each group and the ratios of tumor formation mice are shown. (F) Propagation of patient-derived xenografts after the indicated treatments, which were performed when xenograft volume reach about 400 mm3. In all panels, data are shown as mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001 by 1-way ANOVA. For all representative images, n=3 independent experiments performed with similar results.