| Summary: | 碩士 === 國立清華大學 === 分子與細胞生物研究所 === 101 === The Wnt signaling is involved in many normal developmental processes and human diseases. Recent evidence suggests that the Wnt signaling pathway is critical for reprogramming of stem cell properties in cancer cells. The secreted Frizzled-related protein (sFRP) and Dickkopf (Dkk) family are both antagonists of the Wnt signaling pathway. However, the mechanism of sFRP4 and Dkk1 in the Wnt signaling-dependent reprogramming of stem cell properties is still equivocal.
In this study, we found that extracellular sFRP4 did not associate with Wnt3a. But another Wnt antagonist, Dkk1, repressed the Wnt signaling by directly binding to Wnt3a and consequently abolishing the LRP6-GSK3β signaling activation and β-catenin accumulation in the nucleus. Moreover, sFRP4 could even associate with β-catenin in the cytosol and nucleus to loss β-catenin/TCF transcriptional activities. To characterize the biological effects of sFRP4 on reprogramming of stem cells properties, we found that the association of sFRP4 and β-catenin could diminish cancer-initiating capabilities, characterized by capable of decreasing sphere-forming abilities, expression levels of the ABC transporter family. Taken together, these findings not only establish a central role of sFRP4 in regulating the Wnt signaling-elicited reprogramming of stem cell properties in cancer cells but also shake the dogma of the sFRP family being extracellular antagonists of the Wnt signaling via directly binding to Wnt ligands.
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