Cellular plasticity of trans- and dedifferentiation markers in human hepatoma cells in vitro and in vivo.
Tumor cells have the capability to trans- and to dedifferentiate, for example by reactivating embryonic development genes and stem cell characteristics. The aim of our study was to show the differential expression of stem- and progenitor cell markers in human hepatocellular carcinoma cell lines (HCC). Different human HCC cell lines (HUH7, HUH7 5-15, HUH7 pcDNA3.1, Hep3B and HepG2) were cultured under standard conditions in vitro or implanted subcutaneously (5x10(6) cells) in male NMRI mice. Specimens were characterized by quantitative real-time PCR, Western blotting, methylation-specific PCR and immunohistochemistry for markers of differentiation (cytokeratins, vimentin), embryonic development or stem cells (PTC, PDX-1, SHH, Thy1, c-kit, CD34, beta-catenin, Ki-67). The investigated HCC cell lines showed different patterns of marker expression allowing to distinguish four distinct groups: the classical cholangiocellular type (Huh-7, Huh-7 pcDNA3.1, Hep3B) with expression of CK7/19, beta-catenin and CD34; a dedifferentiated mesenchymal-proliferative type (Huh-7 5-15) characterized by CK19, Vimentin and Ki-67; a dedifferentiated embryonic-development type (Hep3B implanted in matrigel) with expression of CK19, beta-catenin and PTC and a classical HCC type (HepG2) showing CK18/19 and beta-catenin expression. HCC cell lines showed significantly different expression patterns of differentiation markers in a xenograft model. Furthermore, direct association of some markers was observed. The groups differ from each other in expression patterns, but also show that environmental factors play an important role in the behaviour of cells.
Jabari
Samir
S
Department of Medicine 1, University Hospital Erlangen, D-91054 Erlangen, Germany.
Meissnitzer
Matthias
M
Quint
Karl
K
Gahr
Susanne
S
Wissniowski
Till
T
Hahn
Eckhart G
EG
Neureiter
Daniel
D
Ocker
Matthias
M
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054337:Cell Dedifferentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000235:genetics*; D016000:Cluster Analysis; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism
D014408:Biomarkers, Tumor; D012333:RNA, Messenger