Notch信号通路
mTORC1型
癌症研究
克拉斯
PI3K/AKT/mTOR通路
癌变
蛋白激酶B
生物
磷酸化
信号转导
癌症
细胞生物学
结直肠癌
遗传学
作者
Mio Namikawa,Akira Fukuda,Kenta Mizukoshi,Kosuke Iwane,Munenori Kawai,Go Yamakawa,Mayuki Omatsu,Makoto Sono,Tomonori Masuda,Osamu Araki,Munemasa Nagao,Takaaki Yoshikawa,Seishi Ogawa,Yukiko Hiramatsu,Yu Muta,Motoyuki Tsuda,Takahisa Maruno,Yuki Nakanishi,Tatsuaki Tsuruyama,Kojiro Taura,Etsuro Hatano,Hiroshi Seno
摘要
Abstract Biliary tract cancer (BTC) has poor prognosis. The Notch receptor is aberrantly expressed in extrahepatic cholangiocarcinoma (eCCA). However, the role of Notch signaling in the initiation and progression of eCCA and gallbladder (GB) cancer remains unknown. Therefore, we investigated the functional role of Notch signaling during tumorigenesis of the extrahepatic bile duct (EHBD) and GB. Activation of Notch signaling and oncogenic Kras resulted in the development of biliary intraepithelial neoplasia (BilINs) in the EHBD and GB, which were premalignant lesions that progressed to adenocarcinoma in mice. The expression of genes involved in the mTORC1 pathway was increased in biliary spheroids from Hnf1b‐CreERT2 ; Kras LSL‐G12D ; Rosa26 LSL‐NotchIC mice and inhibition of the mTORC1 pathway suppressed spheroid growth. Additionally, simultaneous activation of the PI3K–AKT and Notch pathways in EHBD and GB induced biliary cancer development in mice. Consistent with this, we observed a significant correlation between activated NOTCH1 and phosphorylated Ribosomal Protein S6 (p‐S6) expression in human eCCA. Furthermore, inhibition of the mTORC1 pathway suppressed the growth of Notch‐activated human biliary cancer cells in vitro and in vivo . Mechanistically, the Kras/Notch–Myc axis activated mTORC1 through TSC2 phosphorylation in mutant biliary spheroids. These data indicate that inhibition of the mTORC1 pathway could be an effective treatment strategy for Notch‐activated human eCCA. © 2023 The Pathological Society of Great Britain and Ireland.
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