Yukiko Oya, Junya Arai, Yoku Hayakawa, Toshiro Shiokawa, Shintaro Shinohara, Masahiro Hata, Yuki Matsushita, Hiroto Kinoshita, Chie Uekura, Ken Kurokawa, Sohei Abe, Mayo Tsuboi, Sozaburo Ihara, Nobumi Suzuki, Hayato Hikita, Tetsuro Takehara, Timothy C Wang, Mitsuhiro Fujishiro
Bcl-xL promotes gastric tumorigenesis through dual mechanisms-enhancing Wnt signaling and suppressing PPARγ-and highlight Bcl-xL as a potential therapeutic target while suggesting PPARγ activation may be protective.
BACKGROUND AND AIMS: The Wnt/β-catenin and YAP pathways cooperatively drive gastrointestinal tumor progression. BCL2L1, a YAP target gene, encodes the anti-apoptotic isoform Bcl-xL, which is highly expressed in multiple cancers, but its role in gastric cancer remains unclear.
METHODS: We generated Mist1-CreERT; Apcflox/flox and bcl-xlflox/flox mice to study gastric tumorigenesis with or without Bcl-xL. 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 Bcl-xL 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 Bcl-xL 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. Epidemiological analysis suggested that pioglitazone, a PPARγ agonist, reduced gastric cancer incidence in diabetic patients.
CONCLUSIONS: Bcl-xL promotes gastric tumorigenesis through dual mechanisms-enhancing Wnt signaling and suppressing PPARγ-and highlight Bcl-xL as a potential therapeutic target while suggesting PPARγ activation may be protective.