The expression of Wnt-inhibitor DKK1 (Dickkopf 1) is determined by intercellular crosstalk and hypoxia in human malignant gliomas.
OBJECTIVE
Wnt signalling pathways regulate proliferation, motility and survival in a variety of human cell types. Dickkopf 1 (DKK1) gene codes for a secreted Wnt inhibitory factor. It functions as tumour suppressor gene in breast cancer and as a pro-apoptotic factor in glioma cells. In this study, we aimed to demonstrate whether the different expression of DKK1 in human glioma-derived cells is dependent on microenvironmental factors like hypoxia and regulated by the intercellular crosstalk with bone-marrow-derived mesenchymal stem cells (bmMSCs).


METHODS
Glioma cell line U87-MG, three cell lines from human glioblastoma grade IV (glioma-derived mesenchymal stem cells) and three bmMSCs were selected for the experiment. The expression of DKK1 in cell lines under normoxic/hypoxic environment or co-culture condition was measured using real-time PCR and enzyme-linked immunoadsorbent assay. The effect of DKK1 on cell migration and proliferation was evaluated by in vitro wound healing assays and sulphorhodamine assays, respectively.


RESULTS
Glioma-derived cells U87-MG displayed lower DKK1 expression compared with bmMSCs. Hypoxia led to an overexpression of DKK1 in bmMSCs and U87-MG when compared to normoxic environment, whereas co-culture of U87-MG with bmMSCs induced the expression of DKK1 in both cell lines. Exogenous recombinant DKK1 inhibited cell migration on all cell lines, but did not have a significant effect on cell proliferation of bmMSCs and glioma cell lines.


CONCLUSIONS
In this study, we showed for the first time that the expression of DKK1 was hypoxia dependent in human malignant glioma cell lines. The induction of DKK1 by intracellular crosstalk or hypoxia stimuli sheds light on the intense adaption of glial tumour cells to environmental alterations.
Tumour-Biological Laboratory, Department of Neurosurgery, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany, ketaiguo@gmail.com.
Ke-Tai
KT
Guo
Peng
P
Fu
Kathrin
K
Juerchott
Helena
H
Motaln
Joachim
J
Selbig
Tamara
T
Lah
Jörg-Christian
JC
Tonn
Christian
C
Schichor
D002450:Cell Communication; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism; D060449:Wnt Signaling Pathway
C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins