生物
癌症干细胞
干细胞
分子生物学
癌症研究
人口
克隆(Java方法)
细胞生物学
生物化学
医学
DNA
环境卫生
作者
Wei Ding,Marialena Mouzaki,Hanning You,Joshua C. Laird,José M. Mato,Shelly C. Lu,C. Bart Rountree
出处
期刊:Hepatology
[Wiley]
日期:2008-11-19
卷期号:49 (4): 1277-1286
被引量:90
摘要
Methionine adenosyltransferase (MAT) is an essential enzyme required for S-adenosylmethionine biosynthesis. Hepatic MAT activity falls during chronic liver injury, and mice lacking Mat1a develop spontaneous hepatocellular carcinoma by 18 months. We have previously demonstrated that CD133+CD45− oval cells isolated from 16-month-old Mat1a−/− mice represent a liver cancer stem cell population. The transforming growth factor β (TGF-β) pathway constitutes a central signaling network in proliferation, apoptosis, and tumorigenesis. In this study, we tested the response of tumorigenic liver stem cells to TGF-β. CD133+CD45− oval cells were isolated from premalignant 16-month-old Mat1a−/− mice by flow cytometry and expanded as five clone lines derived from a single cell. All clone lines demonstrated expression of both hepatocyte and cholangiocyte markers and maintained a small population (0.5% to 2%) of CD133+ cells in vitro, and three of five clone lines produced tumors. Although TGF-β1 inhibited cell growth equally in CD133− and CD133+ cells from each clone line, the CD133+ population demonstrated significant resistance to TGF-β–induced apoptosis compared with CD133− cells. Furthermore, CD133+ cells demonstrated a substantial increase in mitogen-activated protein kinase (MAPK) pathway activation, as demonstrated by phosphorylated extracellular signal-regulated kinase levels before and after TGF-β stimulation. MAPK inhibition using mitogen-activated protein kinase kinase 1 (MEK1) inhibitor PD98059 led to a significant increase in TGF-β–induced apoptosis in CD133+ cells. Conversely, a constitutively active form of MEK1 blocked the apoptotic effects of TGF-β in CD133− cells. Conclusion: CD133+ liver cancer stem cells exhibit relative resistance to TGF-β–induced apoptosis. One mechanism of resistance to TGF-β–induced apoptosis in CD133+ cancer stem cells is an activated mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. (HEPATOLOGY 2009.)
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