Loss of Mettl3 enhances liver tumorigenesis by inducing hepatocyte dedifferentiation and hyperproliferation.

Tao Wei, Jin Li, Jian Zhang, Qi Zhang, Xiaoyu Liu, Qi Chen, Liang Wen, Ke Ma, Wen Chen, Jianhui Zhao, Cheng Zhang, Jinyan Huang, Yali Xie, Hao Qin, Danfeng Qian, Tingbo Liang

Cell reports 2023 Jul 25

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While a few works have shown that Mettl3 plays oncogenic roles in hepatocellular carcinoma (HCC), its function in early HCC tumorigenesis remains unclear. In Mettl3flox/flox; Alb-Cre knockout mice, Mettl3 loss leads to aberrant hepatocyte homeostasis and liver damage. Importantly, Mettl3 deletion dramatically accelerates liver tumorigenesis in various HCC mouse models. Depletion of Mettl3 in adult Mettl3flox/flox mice through TBG-Cre administration also enhances liver tumor development, while overexpression of Mettl3 inhibits hepatocarcinogenesis. Mechanistically, aggravated tumorigenesis upon Mettl3 deletion is a consequence of hepatocyte dedifferentiation and hyperproliferation via m6A-mediated modulation on Hnf4α and cell cycle genes. In contrast, by using Mettl3flox/flox; Ubc-Cre mice, depletion of Mettl3 in established HCC ameliorates tumor progression. Additionally, Mettl3 is overexpressed in HCC tumors compared with adjacent non-tumor tissues. The present findings define a tumor-suppressive role of Mettl3 in liver tumorigenesis, indicating its potentially opposite stage-dependent functions in HCC initiation versus progression. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Tao Wei, Jin Li, Jian Zhang, Qi Zhang, Xiaoyu Liu, Qi Chen, Liang Wen, Ke Ma, Wen Chen, Jianhui Zhao, Cheng Zhang, Jinyan Huang, Yali Xie, Hao Qin, Danfeng Qian, Tingbo Liang. Loss of Mettl3 enhances liver tumorigenesis by inducing hepatocyte dedifferentiation and hyperproliferation. Cell reports. 2023 Jul 25;42(7):112704