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

doi:10.1016/j.celrep.2023.112704

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

Cell Rep. 2023 Jul 25;42(7):112704. doi: 10.1016/j.celrep.2023.112704. Epub 2023 Jun 27.

Authors

Tao Wei¹, Jin Li¹, Jian Zhang¹, Qi Zhang¹, Xiaoyu Liu², Qi Chen¹, Liang Wen¹, Ke Ma¹, Wen Chen¹, Jianhui Zhao¹, Cheng Zhang¹, Jinyan Huang¹, Yali Xie¹, Hao Qin¹, Danfeng Qian¹, Tingbo Liang³

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, Zhejiang 310003, China.
² Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, Zhejiang 310003, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310014, China. Electronic address: liangtingbo@zju.edu.cn.

PMID: 37379215
DOI: 10.1016/j.celrep.2023.112704

Abstract

While a few works have shown that Mettl3 plays oncogenic roles in hepatocellular carcinoma (HCC), its function in early HCC tumorigenesis remains unclear. In Mettl3^flox/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 Mettl3^flox/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 Mettl3^flox/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.

Keywords: CP: Cancer; CP: Molecular biology; Hnf4α; Mettl3; context-dependent function; liver cancer; liver damage; m6A modification; tumorigenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / pathology
Carcinoma, Hepatocellular* / metabolism
Cell Transformation, Neoplastic / pathology
Hepatocytes / metabolism
Liver Neoplasms* / pathology
Methyltransferases / genetics
Methyltransferases / metabolism
Mice
Mice, Knockout

Substances

Methyltransferases
Mettl3 protein, mouse