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 9

MAFF serves as a target for liver tumors without MAFA/MAFG CNA.

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MAFF serves as a target for liver tumors without MAFA/MAFG CNA. (A) West...
(A) Western blot for MAFF expression in liver tumor (T) and peri-tumor (P) samples. Typical images are shown in the left panel and signal intensities are in the right panel. (B) Immunofluorescence of CD44 and MAFF in CD44+ TICs and CD44– non-TICs. Scale bars: 10 μm. Sphere formation (C) and transwell (D) detection of HCC primary cells, which were treated with MAFF ASO 1 week before detection. MAFF ASO responders (#1, #3, #4, #6, #8, #9, and #10) are labeled red. Scale bars: 500 μm (C), 70 μm (D). (E) Tumor volume and survival analyses of MAFF ASO–treated primary cells. Patient-derived xenografts were treated with ASO when xenograft volume reached about 400 mm3 (upper panel). Kaplan-Meier survival analysis of n = 7 mice are shown (lower panel). CD44 FACS detection (F) and immunohistochemistry (G) using MAFF ASO–treated and control xenografts. Scale bars: 50 μm. In all panels, data are shown as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. Significance was determined by 1-way ANOVA (E, upper panel), log-rank test (E, lower panel), or 1-tailed Student’s t test (A, C, D, and F). For all representative images, n = 3 independent experiments performed with similar results.