Members of the dickkopf-related protein family (DKK-1, -2, -3, and -4) are secreted proteins with two cysteine-rich domains separated by a linker region. And DKK3 has been proposed as tumour suppressor gene and a marker for tumour blood vessels. DKK3 is the only DKK family member abundantly expressed in normal lung, but silenced by promoter hypermethylation in a large fraction of lung cancer cell lines and lung tumors. Downregulation of DKK3 was correlated with tumor progression and expression of nuclear beta-catenin in lung tumors. Ectopic expression of DKK3 in lung cancer cells with DKK3 hypermethylation induced apoptosis and inhibited TCF-4 activity as well as nuclear accumulation of beta-catenin and expression of TCF-4 targets c-Myc and cyclin D1. DKK3 modulates FGF and Activin/Nodal signaling to regulate mesoderm induction during early Xenopus development, was reported.
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