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

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• ARID1A mutations are common in cancers, but its role in environmental carcinogenesis is unclear.
• SWI/SNF complex dysfunction due to ARID1A loss may impact tumor initiation.
• Environmental carcinogens like aristolochic acid I (AAI) pose a risk for liver diseases.

Purpose of the Study:

• To investigate the role of ARID1A deficiency in AAI-induced hepatocarcinogenesis.
• To elucidate the molecular mechanisms linking ARID1A loss, AAI exposure, and liver tumor development.
• To explore therapeutic strategies targeting ARID1A-deficient liver cancer.

Main Methods:

• Utilized liver-specific Arid1a-deficient (Arid1a^LKO) mice exposed to AAI.
• Employed single-nucleus RNA-sequencing and phylogenetic analyses.
• Investigated the effect of beta-catenin signaling inhibition on tumor growth.

Main Results:

• AAI exposure dramatically accelerated hepatocarcinogenesis in Arid1a-deficient livers.
• A specific 3' splice-site mutation in Ctnnb1, leading to beta-catenin activation, was observed in most tumors.
• Arid1a deficiency impaired nucleotide excision repair and enhanced AAI bioactivation, creating a dual-hit mechanism for carcinogenesis.
• Beta-catenin inhibition significantly suppressed AAI-induced tumors in Arid1a-deficient mice.

Conclusions:

• ARID1A acts as a guardian against environmental carcinogens by maintaining DNA repair and limiting genotoxicity.
• A dual-hit mechanism involving impaired DNA repair and heightened genotoxicity drives synergistic carcinogenesis in ARID1A-deficient livers exposed to AAI.
• Beta-catenin blockade is a promising strategy for precision prevention in individuals with ARID1A-mutant benign liver diseases and high environmental carcinogen exposure.