Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations.
Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations.
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DOI：
10.1016/j.jhep.2010.12.043
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发表时间：
2011-10
影响因子：
25.7
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Chen X;Lingala S;Khoobyari S;Nolta J;Zern MA;Wu J
我们的前期研究表明，CD 133、EpCAM和乙醛脱氢酶（ALDH）是鉴定肝细胞癌（HCC）组织中肿瘤干细胞（CSCs）的有用标志物。本研究的目的是评估化疗敏感性和肿瘤侵袭能力的基础上CSC标志物谱，并探讨潜在的分子机制。根据CD 133、EpCAM和ALDH表达谱将肝癌细胞系分成亚群。上皮间质转化（EMT）和刺猬（Hh）信号进行了检查，以确定其与化疗耐药性和侵略性入侵的联系。分化良好的细胞系对CD 133 +/ALDH高和CD 133 +/EpCAM+呈阳性，分别为1.5-15%和2.3-8.3%;而分化不良的细胞对这些标志物几乎全部呈阴性。FACS富集的CD 133 +/ALDHhigh和CD 133 +/EpCAM+ Hep 3B和Huh-7细胞在体外形成更多的球状体。CD 133 −/ALDHlow HLE细胞对顺铂、多柔比星或索拉非尼的耐药性高于其阳性对应物。CD 133 −/EpCAM− Huh-7细胞或CD 133 −/ALDH− HLE细胞比其阳性对应物表现出更高的侵袭率。HLE和HLF细胞在双阴性亚群中获得EMT。Huh-7 CD 133 −/EpCAM−细胞中的Hh活性高于其阳性对应物，环巴胺抑制Hh活性导致细胞增殖减少。分化良好的CD 133 +/ALDHhigh或CD 133 +/EpCAM+细胞似乎是CSC/起始亚群;而在分化不良的肝癌细胞中，EMT和增强的hedgehog信号传导活性可能是其化学抗性和侵袭的原因。这些发现强调了EMT和增强的Hh信号在肝癌干细胞或起始细胞中的重要性。
Our previous studies showed that CD133, EpCAM and aldehyde dehydrogenase (ALDH) are useful markers to identify cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) tissues. The present study aims to evaluate chemosensitivity and invasion capability of HCC based on CSC marker profiles, and to explore underlying molecular mechanisms. Hepatoma cell lines were separated into subpopulations according to CD133, EpCAM and ALDH expression profiles. Epithelial mesenchymal transition (EMT) and hedgehog (Hh) signaling were examined to identify their links with chemoresistance and aggressive invasion. Well-differentiated cell lines were positive for CD133+/ALDHhigh and CD133+/EpCAM+ at 1.5–15% and 2.3–8.3%; whereas, poorly-differentiated cells were almost all negative for these markers. FACS-enriched CD133+/ALDHhigh and CD133+/EpCAM+ Hep3B and Huh-7 cells formed more spheroids in vitro. CD133−/ALDHlow HLE cells were more resistant to cisplatin, doxorubicin or sorafenib than their positive counterparts. CD133−/EpCAM− Huh-7 cells or CD133−/ALDH− HLE cells exhibited a higher invasion rate than their positive counterparts. HLE and HLF cells acquired EMT in double negative subpopulations. Hh activity in Huh-7 CD133−/EpCAM− cells was higher than in their positive counterparts, and the inhibition of Hh activity by cyclopamine resulted in reduced cell proliferation. Well-differentiated CD133+/ALDHhigh or CD133+/EpCAM+ cells appear to be a CSC/initiating subpopulation; whereas, in poorly-differentiated hepatoma cells, EMT and enhanced hedgehog signaling activity may be responsible for their chemoresistance and invasion. These findings underscore the significance of EMT and enhanced Hh signaling in liver cancer stem or initiating cells.