Document Detail


Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations.
MedLine Citation:
PMID:  21334406     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: 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 the underlying molecular mechanisms.
METHODS: 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.
RESULTS: Well-differentiated cell lines were positive for CD133(+)/ALDH(high) 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(+)/ALDH(high) and CD133(+)/EpCAM(+) Hep3B and Huh-7 cells formed more spheroids in vitro. CD133(-)/ALDH(low) 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.
CONCLUSIONS: Well-differentiated CD133(+)/ALDH(high) 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.
Authors:
Xiaoli Chen; Shilpa Lingala; Shiva Khoobyari; Jan Nolta; Mark A Zern; Jian Wu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-02-18
Journal Detail:
Title:  Journal of hepatology     Volume:  55     ISSN:  1600-0641     ISO Abbreviation:  J. Hepatol.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-09-19     Completed Date:  2011-11-21     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  8503886     Medline TA:  J Hepatol     Country:  England    
Other Details:
Languages:  eng     Pagination:  838-45     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 European Association for the Study of the Liver. All rights reserved.
Affiliation:
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California, Davis Medical Center, Sacramento, CA 95817, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD / metabolism
Antineoplastic Agents / pharmacology
Carcinoma, Hepatocellular* / drug therapy,  pathology,  physiopathology
Cell Differentiation / physiology
Cell Line, Tumor
Drug Resistance, Neoplasm / physiology*
Epithelial-Mesenchymal Transition / physiology*
Flow Cytometry
Glycoproteins / metabolism
Hedgehog Proteins / metabolism*
Humans
Liver Neoplasms* / drug therapy,  pathology,  physiopathology
Mice
Neoplasm Invasiveness
Peptides / metabolism
Signal Transduction / physiology
Wound Healing / physiology
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
R01 DK075415/DK/NIDDK NIH HHS; R01 DK075415-03/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/AC133 antigen; 0/Antigens, CD; 0/Antineoplastic Agents; 0/Glycoproteins; 0/Hedgehog Proteins; 0/Peptides
Comments/Corrections
Erratum In:
J Hepatol. 2013 Feb;58(2):405

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