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 3

cia-maf–KO mice harbor impaired liver tumorigenesis and self-renewal capacities.

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cia-maf–KO mice harbor impaired liver tumorigenesis and self-renewal ca...
(A) Schematic diagram of DEN/CCl4 liver tumorigenesis. WT and cia-maf KO mice were used. (B) Tumor numbers of WT and cia-maf KO mice at 32 weeks. n = 14 mice were detected for each group. Data are shown as mean ± SD. **P < 0.01, by 1-tailed Student’s t test. (C) Typical images of CPS1, TBX3, GS1, TUNEL, F4/80, and Sirius Red staining in WT and cia-maf–KO peri-tumor liver tissues, which were performed using DEN/CCl4-induced livers. Scale bars: 50 μm. (D) Typical images of CD34, CD44, Ki67, Ccnd2, TUNEL, F4/80, and Sirius Red staining in WT and cia-maf–KO tumors. All samples were derived from DEN/CCl4-treated mice. Scale bars: 20 μm. (E) Sphere formation assay of WT and cia-maf–KO TICs, which was sorted from WT and cia-maf–KO tumors. Scale bars: 500 μm. (F) FISH for cia-maf expression and immunofluorescence for CD44 expression in WT and cia-maf–KO spheres. Scale bars: 10 μm. (G) HrasG12V and shP53 plasmid, along with luciferase and SB transposase plasmid, were injected into cia-maf–KO and littermate mice, and tumor propagation was measured via luciferase signals. For C and D, n = 10 images taken with similar results. For E and F, n = 3 independent experiments performed with similar results. For G, n = 10 mice per group.