BACKGROUND & AIMS: The Wnt-β-catenin and Yes-associated protein pathways cooperatively drive gastrointestinal tumor progression. BCL2L1, a Yes-associated protein target gene, encodes the anti-apoptotic isoform B-cell lymphoma-extra-large, which is highly expressed in multiple cancers, but its role in gastric cancer remains unclear. METHODS: mice to study gastric tumorigenesis with or without B-cell lymphoma-extra-large. Gastric organoids and xenografts were used to assess proliferation and downstream signaling, and findings were validated in human gastric cancer tissues and databases. RESULTS: Deletion of B-cell lymphoma-extra-large significantly reduced tumor growth and proliferation in Apc-deficient tumors, organoids, and xenografts. Nuclear β-catenin and Wnt target gene expression were attenuated, partly through derepression of Hnf4a and Pparg, indicating that B-cell lymphoma-extra-large promotes Wnt signaling. Concurrently, downregulation of Hnf4a and Pparg contributes to the inhibition of multiple metabolic pathways. In human gastric cancer, high BCL2L1 expression correlated with elevated Wnt target genes and poor prognosis, whereas PPARG expression inversely correlated with BCL2L1 and associated with favorable outcomes. Epidemiologic analysis suggested that pioglitazone, a peroxisome proliferator-activated receptor γ agonist, reduced gastric cancer incidence in diabetic patients. CONCLUSIONS: B-cell lymphoma-extra-large promotes gastric tumorigenesis through dual mechanisms-enhancing Wnt signaling and suppressing peroxisome proliferator-activated receptor γ-and highlight B-cell lymphoma-extra-large as a potential therapeutic target while suggesting peroxisome proliferator-activated receptor γ activation may be protective.
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Oya et al. (2026) studied this question.
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