Circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF
Zhenzhen Chen, Tiankun Lu, Lan Huang, Zhiwei Wang, Zhongyi Yan, Yubo Guan, Wenjing Hu, Zusen Fan, Pingping Zhu
Zhenzhen Chen, Tiankun Lu, Lan Huang, Zhiwei Wang, Zhongyi Yan, Yubo Guan, Wenjing Hu, Zusen Fan, Pingping Zhu
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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 5

cia-MAF targets MAFF to initiate TIC self-renewal.

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cia-MAF targets MAFF to initiate TIC self-renewal. (A) Heatmap of TF exp...
(A) Heatmap of TF expression levels in WT and cia-maf–KO liver TICs. The top 10 TFs with decreased expression in cia-maf–KO liver TICs are listed in the right panel. For WT and cia-maf–KO liver TICs, liver TICs from 5 mice were pooled together for RNA-seq. WT littermates were used as controls. (B) Sphere formation of primary cells in which the indicated TFs were silenced individually. Scale bars: 500 μm. (C) Western blot to detect knockout efficiency using MAFF-KO and control cells. β-actin was a loading control. (D) CD44 FACS for liver TICs in MAFF-KO and control cells. Typical images are shown in the left panel and TIC ratios are shown in the right panel. (E) Sphere formation of MAFF-KO cells. Representative sphere photos are in the left panel and sphere formation ratios are in the right panel. Each group used 5000 cells. Scale bars: 500 μm. In all panels, data are shown as mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001 by 1-way ANOVA. For B–E, n = 3 independent experiments performed with similar results.