Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations

Xiaoli Chen, Shilpa Lingala, Shiva Khoobyari, Jan Nolta, Mark A Zern, Jian Wu

Research output: Contribution to journalArticlepeer-review

160 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)838-845
Number of pages8
JournalJournal of Hepatology
Issue number4
StatePublished - Oct 2011


  • Cancer stem cells
  • Chemoresistance
  • Epithelial mesenchymal transition
  • Hedgehog signaling
  • Hepatocellular carcinoma

ASJC Scopus subject areas

  • Hepatology


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