MAD2L1 supports MYC-driven liver carcinogenesis in mice and predicts poor prognosis in human hepatocarcinoma.

Autor:	Lu X; Department of Biliary-Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China., Zhang Y; Cancer Biology Program, University of Hawai'i Cancer Center, University of Hawai'i, Honolulu, HA 96813, United States., Xue J; Department of Biliary-Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China., Evert M; Institute of Pathology, University of Regensburg, Regensburg 93053, Germany., Calvisi D; Institute of Pathology, University of Regensburg, Regensburg 93053, Germany., Chen X; Cancer Biology Program, University of Hawai'i Cancer Center, University of Hawai'i, Honolulu, HA 96813, United States., Wang X; Cancer Biology Program, University of Hawai'i Cancer Center, University of Hawai'i, Honolulu, HA 96813, United States.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2025 Jan 01; Vol. 203 (1), pp. 41-51.
DOI:	10.1093/toxsci/kfae126
Abstrakt:	Mitotic arrest-deficient 2 like 1 (MAD2L1) is a component of the mitotic spindle assembly checkpoint implicated in cancer cell proliferation and tumorigenesis. The functional role of MAD2L1 in hepatocellular carcinoma (HCC) has not been adequately investigated, especially in vivo. In the current manuscript, we sought to address the function of MAD2L1 in hepatocarcinogenesis. We found that MAD2L1 expression is upregulated in human HCCs, where its expression is associated with higher aggressive tumor grade, elevated proliferative activity, and poor prognosis. In human HCC cell lines, MAD2L1 knockdown led to decreased cell growth. Moreover, RNA-seq results demonstrated that MAD2L1 silencing induces the expression of genes associated with cell cycle, DNA replication, and various cancer-related pathways, supporting the critical role of MAD2L1 during HCC growth and differentiation. In a c-MYC-induced mouse HCC model, we revealed an increased expression of Mad2l1. Furthermore, Mad2l1 CRIPSR-mediated silencing prevented c-MYC-driven mouse liver development. Altogether, our study suggests that MAD2L1 plays a crucial role in hepatocarcinogenesis, and that its suppression could be a promising therapeutic strategy for treating human HCC. MAD2L1 plays a critical role in liver cancer development, silencing MAD2L1 reduced cell growth in vitro and inhibited c-MYC-driven liver cancer development in vivo. MAD2L1 suppression might be a promising therapeutic approach for treating human liver cancer. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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