ASIA unversity:Item 310904400/4571
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    题名: Bile acid exposure up-regulates tuberous sclerosis complex 1/mammalian target of rapamycin pathway in Barrett's-associated esophageal adenocarcinoma
    作者: Chia-Jui Yen;Julie G. Izzo;Dung-Fang Lee;Sushovan Guha;Yongkun Wei;Tsung-Te Wu;Chun-Te Chen;Hsu-Ping Kuo;Jung-Mao Hsu;Hui-Lung Sun;Chao-Kai Chou;Navtej S. Buttar;Kenneth K. Wang;Peng Huang;Jaffer Ajani;Mien-Chie Hung
    关键词: bile acid;IKK?/TSC1/mTOR;Barrett's associated esophageal adenocarcinoma
    日期: 2008-04
    上传时间: 2009-11-27 13:56:52 (UTC+8)
    出版者: Asia University
    摘要: Barrett's esophagus, a columnar metaplasia of the lower esophagus epithelium related to gastroesophageal reflux disease, is the strongest known risk factor for the development of esophageal adenocarcinoma (EAC). Understanding the signal transduction events involved in esophageal epithelium carcinogenesis may provide insights into the origins of EAC and may suggest new therapies. To elucidate the molecular pathways of bile acid?induced tumorigenesis, the newly identified inflammation-associated signaling pathway involving IB kinases ? (IKK?), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1) was confirmed to be activated in immortalized Barrett's CPC-A and CPC-C cells and esophageal cancer SEG-1 and BE3 cells. Phosphorylation of TSC1 and S6K1 was induced in response to bile acid stimulation. Treatment of these cells with the mTOR inhibitor rapamycin or the IKK? inhibitor Bay 11-7082 suppressed bile acid?induced cell proliferation and anchorage-independent growth. We next used an orthotopic rat model to evaluate the role of bile acid in the progression of Barrett's esophagus to EAC. Of interest, we found high expression of phosphorylated IKK? (pIKK?) and phosphorylated S6K1 (pS6K1) in tumor tissues and the Barrett's epithelium compared with normal epithelium. Furthermore, immunostaining of clinical EAC tissue specimens revealed that pIKK? expression was strongly correlated with pS6K1 level. Together, these results show that bile acid can deregulate TSC1/mTOR through IKK? signaling, which may play a critical role in EAC progression. In addition, Bay 11-7082 and rapamycin may potentially be chemopreventive drugs against Barrett's esophagus?associated EAC. [Cancer Res 2008;68(8):2632?40]
    關聯: CANCER RESEARCH 68(8):2632-2640
    显示于类别:[生物科技學系] 期刊論文


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