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Abstract
Abstract Within the gastrointestine, nerves help to regulate both normal and neoplastic stem cell dynamics. Several previous studies suggested that cholinergic nerve signaling plays an important role in gastrointestinal cancer development, but the exact underlying mechanism has not been clarified. In this study, we examined the role of muscarinic acetylcholine receptor subtype 3 (M3R) in gastric homeostasis and cancer development by using mouse models and human cancer cell lines. In situ hybridization revealed M3R expression in gastric stem cell zone, and its expression was markedly upregulated in gastric cancer cells. We knocked out M3R in Lgr5+ gastric stem cells in Lgr5-CreERT; M3Rflox/flox mice, and found that deletion of M3R inhibited clonal expansion of Lgr5+ cells in regenerative states. In a gastric tumor model of Mist1-CreERT; Apcflox/flox mice, knockout of M3R dramatically suppressed tumor growth. RNA sequencing analysis of these tumors revealed that several important pathways were significantly inhibited in M3R knockout samples, including YAP/TAZ pathway. We established M3R-expressing gastric cancer cell lines, and western blotting, luciferase assay, and RT-PCR analysis confirmed that acetylcholine (ACh) agonist activates YAP pathway through M3R. YAP is upregulated in approximately half of gastric cancer patients, and its expression is significantly associated with disease stage and histological form. This M3R-YAP axis activates the gastric stem cell niche and offers a compelling target for tumor treatment and prevention. Note: This abstract was not presented at the meeting. Citation Format: Yoku Hayakawa, Mitsuru Konishi, Kosuke Sakitani, Kazuhiko Koike, Timothy Wang. Muscarinic acetylcholine receptor subtype 3 regulates gastric stem cell expansion and gastric cancer progression by controlling YAP activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3339. doi:10.1158/1538-7445.AM2017-3339
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