Arid1a Deficiency Drives Aristolochic Acid-Induced Liver Tumorigenesis through Ctnnb1 Mutation and Defective Nucleotide Excision Repair.

ABSTRACT: ARID1A, which encodes an important subunit of SWI/SNF complex, is frequently mutated in non-malignant tissues and tumors. However, how ARID1A loss enables environmental carcinogens to initiate tumorigenesis remains unknown. Here, liver-specific Arid1a-deficient (Arid1a^LKO) mice are exposed to aristolochic acid I (AAI), a potent herbal carcinogen. Notably, AAI dramatically accelerated hepatocarcinogenesis in Arid1a-deficient livers, accompanied by a specific 3' splice-site mutation in Ctnnb1 in most tumors and adjacent non-tumorous tissues. This mutation results in exon 3 skipping and subsequent β-catenin activation. Single-nucleus RNA-seq coupled with phylogenetic analyses reveals AAI-induced tumor microenvironment alteration and clonal expansion of β-catenin-activated cells. Co

SUBMITTER: Wang L 

PROVIDER: S-EPMC12806303 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature