Forced activation of β-catenin signaling supports the transformation of hTERT-immortalized human fetal hepatocytes.
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Forced activation of β-catenin signaling supports the transformation of hTERT-immortalized human fetal hepatocytes. / Wege, Henning; Heim, Denise; Lütgehetmann, Marc; Dierlamm, Judith; Lohse, Ansgar W.; Brümmendorf, Tim H.
In: MOL CANCER RES, Vol. 9, No. 9, 9, 2011, p. 1222-1231.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Forced activation of β-catenin signaling supports the transformation of hTERT-immortalized human fetal hepatocytes.
AU - Wege, Henning
AU - Heim, Denise
AU - Lütgehetmann, Marc
AU - Dierlamm, Judith
AU - Lohse, Ansgar W.
AU - Brümmendorf, Tim H
PY - 2011
Y1 - 2011
N2 - Hepatocarcinogenesis is a multistep process driving the progressive transformation of normal liver cells into highly malignant derivatives. Unlimited proliferation and telomere maintenance have been recognized as prerequisites for the development of liver cancer. Moreover, recent studies identified illegitimate ?-catenin signaling as relevant hit in a considerable subset of patients. To further investigate the currently not well-understood malignant evolution driven by telomerase and ?-catenin, we monitored cytogenetic and phenotypic alterations in untransformed telomerase-immortalized human fetal hepatocytes following forced activation of ?-catenin signaling. As expected, constitutive activation of ?-catenin signaling significantly enhanced proliferation with decreasing serum dependence. Previously intact contact inhibition was almost completely eliminated. Interestingly, after several passages in cell culture, immortalized clones with dominant-positive ?-catenin signaling acquired additional chromosomal aberrations, in particular translocations, anchorage-independent growth capabilities, and formed tumors in athymic nude mice. In further support for the driving role of ?-catenin during hepatocarcinogenesis, improved colony growth in soft agar and accelerated tumor formation was also confirmed in Huh7 cells following stable expression of the constitutively active S33Y ?-catenin mutant. Telomerase inhibition showed that short-term expansion of transformed clones was not telomerase dependent. Finally, cancer pathway profiling in derived tumors revealed upregulation of characteristic genes associated with invasion and angiogenesis. In conclusion, illegitimate activation of ?-catenin signaling enhances the transformation from immortalization to malignant growth in human fetal hepatocytes. Our data functionally confirm a permissive role for ?-catenin signaling in the initial phase of hepatocarcinogenesis.
AB - Hepatocarcinogenesis is a multistep process driving the progressive transformation of normal liver cells into highly malignant derivatives. Unlimited proliferation and telomere maintenance have been recognized as prerequisites for the development of liver cancer. Moreover, recent studies identified illegitimate ?-catenin signaling as relevant hit in a considerable subset of patients. To further investigate the currently not well-understood malignant evolution driven by telomerase and ?-catenin, we monitored cytogenetic and phenotypic alterations in untransformed telomerase-immortalized human fetal hepatocytes following forced activation of ?-catenin signaling. As expected, constitutive activation of ?-catenin signaling significantly enhanced proliferation with decreasing serum dependence. Previously intact contact inhibition was almost completely eliminated. Interestingly, after several passages in cell culture, immortalized clones with dominant-positive ?-catenin signaling acquired additional chromosomal aberrations, in particular translocations, anchorage-independent growth capabilities, and formed tumors in athymic nude mice. In further support for the driving role of ?-catenin during hepatocarcinogenesis, improved colony growth in soft agar and accelerated tumor formation was also confirmed in Huh7 cells following stable expression of the constitutively active S33Y ?-catenin mutant. Telomerase inhibition showed that short-term expansion of transformed clones was not telomerase dependent. Finally, cancer pathway profiling in derived tumors revealed upregulation of characteristic genes associated with invasion and angiogenesis. In conclusion, illegitimate activation of ?-catenin signaling enhances the transformation from immortalization to malignant growth in human fetal hepatocytes. Our data functionally confirm a permissive role for ?-catenin signaling in the initial phase of hepatocarcinogenesis.
KW - Animals
KW - Humans
KW - Mice
KW - Chromosome Aberrations
KW - Signal Transduction
KW - Gene Expression Regulation, Neoplastic
KW - Mice, Nude
KW - Cell Transformation, Neoplastic/genetics
KW - Fetus/cytology/metabolism
KW - Hepatocytes/cytology/metabolism
KW - Liver Neoplasms/genetics/metabolism/pathology
KW - Neoplasm Invasiveness/genetics
KW - Neovascularization, Pathologic/genetics
KW - Telomerase/genetics/metabolism
KW - Transcriptional Activation
KW - beta Catenin/genetics/metabolism
KW - Animals
KW - Humans
KW - Mice
KW - Chromosome Aberrations
KW - Signal Transduction
KW - Gene Expression Regulation, Neoplastic
KW - Mice, Nude
KW - Cell Transformation, Neoplastic/genetics
KW - Fetus/cytology/metabolism
KW - Hepatocytes/cytology/metabolism
KW - Liver Neoplasms/genetics/metabolism/pathology
KW - Neoplasm Invasiveness/genetics
KW - Neovascularization, Pathologic/genetics
KW - Telomerase/genetics/metabolism
KW - Transcriptional Activation
KW - beta Catenin/genetics/metabolism
M3 - SCORING: Journal article
VL - 9
SP - 1222
EP - 1231
JO - MOL CANCER RES
JF - MOL CANCER RES
SN - 1541-7786
IS - 9
M1 - 9
ER -
